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1
Olsen, Oddrun Elise, Hanne Hella, Samah Elsaadi, Carsten Jacobi, Erik Martinez-Hackert, and Toril Holien. "Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors." Biomolecules 10, no. 4 (March 29, 2020): 519. http://dx.doi.org/10.3390/biom10040519.
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Activins belong to the transforming growth factor (TGF)-β family of multifunctional cytokines and signal via the activin receptors ALK4 or ALK7 to activate the SMAD2/3 pathway. In some cases, activins also signal via the bone morphogenetic protein (BMP) receptor ALK2, causing activation of the SMAD1/5/8 pathway. In this study, we aimed to dissect how activin A and activin B homodimers, and activin AB and AC heterodimers activate the two main SMAD branches. We compared the activin-induced signaling dynamics of ALK4/7-SMAD2/3 and ALK2-SMAD1/5 in a multiple myeloma cell line. Signaling via the ALK2-SMAD1/5 pathway exhibited greater differences between ligands than signaling via ALK4/ALK7-SMAD2/3. Interestingly, activin B and activin AB very potently activated SMAD1/5, resembling the activation commonly seen with BMPs. As SMAD1/5 was also activated by activins in other cell types, we propose that dual specificity is a general mechanism for activin ligands. In addition, we found that the antagonist follistatin inhibited signaling by all the tested activins, whereas the antagonist cerberus specifically inhibited activin B. Taken together, we propose that activins may be considered dual specificity TGF-β family members, critically affecting how activins may be considered and targeted clinically.
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Xie, Chen, Wenjuan Jiang, Jerome J. Lacroix, Yun Luo, and Jijun Hao. "Insight into Molecular Mechanism for Activin A-Induced Bone Morphogenetic Protein Signaling." International Journal of Molecular Sciences 21, no. 18 (September 5, 2020): 6498. http://dx.doi.org/10.3390/ijms21186498.
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Activins transduce the TGF-β pathway through a heteromeric signaling complex consisting of type I and type II receptors, and activins also inhibit bone morphogenetic protein (BMP) signaling mediated by type I receptor ALK2. Recent studies indicated that activin A cross-activates the BMP pathway through ALK2R206H, a mutation associated with Fibrodysplasia Ossificans Progressiva (FOP). How activin A inhibits ALK2WT-mediated BMP signaling but activates ALK2R206H-mediated BMP signaling is not well understood, and here we offer some insights into its molecular mechanism. We first demonstrated that among four BMP type I receptors, ALK2 is the only subtype able to mediate the activin A-induced BMP signaling upon the dissociation of FKBP12. We further showed that BMP4 does not cross-signal TGF-β pathway upon FKBP12 inhibition. In addition, although the roles of type II receptors in the ligand-independent BMP signaling activated by FOP-associated mutant ALK2 have been reported, their roles in activin A-induced BMP signaling remains unclear. We demonstrated in this study that the known type II BMP receptors contribute to activin A-induced BMP signaling through their kinase activity. Together, the current study provided important mechanistic insights at the molecular level into further understanding physiological and pathophysiological BMP signaling.
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Lebrun, Jean-Jacques, Kazuaki Takabe, Yan Chen, and Wylie Vale. "Roles of Pathway-Specific and Inhibitory Smads in Activin Receptor Signaling." Molecular Endocrinology 13, no. 1 (January 1, 1999): 15–23. http://dx.doi.org/10.1210/mend.13.1.0218.
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Abstract Activins and other members of the transforming growth factor-β-like superfamily of growth factors transduce their signals by interacting with two types of receptor serine/threonine kinases. The Smad proteins, a new family of intracellular mediators are involved in the signaling pathways of these receptors, but the initial stages of their activation as well as their specific functions remain to be defined. We report here that the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. This complex formation is rapid but also transient. Indeed, soon after their association with the activin receptor, Smad2 and Smad3 are released into the cytoplasm where they interact with the common partner Smad4. These Smad complexes then mediate activin-induced transcription. Finally, we show that the inhibitory Smad7 can prevent the association of the two pathway-specific Smads with the activin receptor complex, thereby blocking the activin signal.
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Jung, Jae Woo, Chihoon Ahn, Sun Young Shim, Peter C. Gray, Witek Kwiatkowski, and Senyon Choe. "Regulation of FSHβ induction in LβT2 cells by BMP2 and an Activin A/BMP2 chimera, AB215." Journal of Endocrinology 223, no. 1 (August 6, 2014): 35–45. http://dx.doi.org/10.1530/joe-14-0317.
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Activins and bone morphogenetic proteins (BMPs) share activin type 2 signaling receptors but utilize different type 1 receptors and Smads. We designed AB215, a potent BMP2-like Activin A/BMP2 chimera incorporating the high-affinity type 2 receptor-binding epitope of Activin A. In this study, we compare the signaling properties of AB215 and BMP2 in HEK293T cells and gonadotroph LβT2 cells in which Activin A and BMP2 synergistically induce FSHβ. In HEK293T cells, AB215 is more potent than BMP2 and competitively blocks Activin A signaling, while BMP2 has a partial blocking activity. Activin A signaling is insensitive to BMP pathway antagonism in HEK293T cells but is strongly inhibited by constitutively active (CA) BMP type 1 receptors. By contrast, the potencies of AB215 and BMP2 are indistinguishable in LβT2 cells and although AB215 blocks Activin A signaling, BMP2 has no inhibitory effect. Unlike HEK293T, Activin A signaling is strongly inhibited by BMP pathway antagonism in LβT2 cells but is largely unaffected by CA BMP type 1 receptors. BMP2 increases phospho-Smad3 levels in LβT2 cells, in both the absence and the presence of Activin A treatment, and augments Activin A-induced FSHβ. AB215 has the opposite effect and sharply decreases basal phospho-Smad3 levels and blocks Smad2 phosphorylation and FSHβ induction resulting from Activin A treatment. These findings together demonstrate that while AB215 activates the BMP pathway, it has opposing effects to those of BMP2 on FSHβ induction in LβT2 cells apparently due to its ability to block Activin A signaling.
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Tang, Pei, Xueer Wang, Min Zhang, Simin Huang, Chuxi Lin, Fang Yan, Ying Deng, Lu Zhang, and Lin Zhang. "Activin B Stimulates Mouse Vibrissae Growth and Regulates Cell Proliferation and Cell Cycle Progression of Hair Matrix Cells through ERK Signaling." International Journal of Molecular Sciences 20, no. 4 (February 15, 2019): 853. http://dx.doi.org/10.3390/ijms20040853.
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Activins and their receptors play important roles in the control of hair follicle morphogenesis, but their role in vibrissae follicle growth remains unclear. To investigate the effect of Activin B on vibrissae follicles, the anagen induction assay and an in vitro vibrissae culture system were constructed. Hematoxylin and eosin staining were performed to determine the hair cycle stages. The 5-ethynyl-2′-deoxyuridine (EdU) and Cell Counting Kit-8 (CCK-8) assays were used to examine the cell proliferation. Flow cytometry was used to detect the cell cycle phase. Inhibitors and Western blot analysis were used to investigate the signaling pathway induced by Activin B. As a result, we found that the vibrissae follicle growth was accelerated by 10 ng/mL Activin B in the anagen induction assay and in an organ culture model. 10 ng/mL Activin B promoted hair matrix cell proliferation in vivo and in vitro. Moreover, Activin B modulates hair matrix cell growth through the ERK–Elk1 signaling pathway, and Activin B accelerates hair matrix cell transition from the G1/G0 phase to the S phase through the ERK–Cyclin D1 signaling pathway. Taken together, these results demonstrated that Activin B may promote mouse vibrissae growth by stimulating hair matrix cell proliferation and cell cycle progression through ERK signaling.
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Roh, Jason D., Ryan Hobson, Vinita Chaudhari, Pablo Quintero, Ashish Yeri, Mark Benson, Chunyang Xiao, et al. "Activin type II receptor signaling in cardiac aging and heart failure." Science Translational Medicine 11, no. 482 (March 6, 2019): eaau8680. http://dx.doi.org/10.1126/scitranslmed.aau8680.
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Activin type II receptor (ActRII) ligands have been implicated in muscle wasting in aging and disease. However, the role of these ligands and ActRII signaling in the heart remains unclear. Here, we investigated this catabolic pathway in human aging and heart failure (HF) using circulating follistatin-like 3 (FSTL3) as a potential indicator of systemic ActRII activity. FSTL3 is a downstream regulator of ActRII signaling, whose expression is up-regulated by the major ActRII ligands, activin A, circulating growth differentiation factor-8 (GDF8), and GDF11. In humans, we found that circulating FSTL3 increased with aging, frailty, and HF severity, correlating with an increase in circulating activins. In mice, increasing circulating activin A increased cardiac ActRII signaling and FSTL3 expression, as well as impaired cardiac function. Conversely, ActRII blockade with either clinical-stage inhibitors or genetic ablation reduced cardiac ActRII signaling while restoring or preserving cardiac function in multiple models of HF induced by aging, sarcomere mutation, or pressure overload. Using unbiased RNA sequencing, we show that activin A, GDF8, and GDF11 all induce a similar pathologic profile associated with up-regulation of the proteasome pathway in mammalian cardiomyocytes. The E3 ubiquitin ligase, Smurf1, was identified as a key downstream effector of activin-mediated ActRII signaling, which increased proteasome-dependent degradation of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), a critical determinant of cardiomyocyte function. Together, our findings suggest that increased activin/ActRII signaling links aging and HF pathobiology and that targeted inhibition of this catabolic pathway holds promise as a therapeutic strategy for multiple forms of HF.
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Qiu, Wanglong, Chia-Yu Kuo, Yu Tian, and Gloria H. Su. "Dual Roles of the Activin Signaling Pathway in Pancreatic Cancer." Biomedicines 9, no. 7 (July 14, 2021): 821. http://dx.doi.org/10.3390/biomedicines9070821.
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Activin, a member of the TGF-β superfamily, is involved in many physiological processes, such as embryonic development and follicle development, as well as in multiple human diseases including cancer. Genetic mutations in the activin signaling pathway have been reported in many cancer types, indicating that activin signaling plays a critical role in tumorigenesis. Recent evidence reveals that activin signaling may function as a tumor-suppressor in tumor initiation, and a promoter in the later progression and metastasis of tumors. This article reviews many aspects of activin, including the signaling cascade of activin, activin-related proteins, and its role in tumorigenesis, particularly in pancreatic cancer development. The mechanisms regulating its dual roles in tumorigenesis remain to be elucidated. Further understanding of the activin signaling pathway may identify potential therapeutic targets for human cancers and other diseases.
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Mallick, Sreeradha, Eric Kenney, and Ioannis Eleftherianos. "The Activin Branch Ligand Daw Regulates the Drosophila melanogaster Immune Response and Lipid Metabolism against the Heterorhabditis bacteriophora Serine Carboxypeptidase." International Journal of Molecular Sciences 25, no. 14 (July 21, 2024): 7970. http://dx.doi.org/10.3390/ijms25147970.
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Despite impressive advances in the broad field of innate immunity, our understanding of the molecules and signaling pathways that control the host immune response to nematode infection remains incomplete. We have shown recently that Transforming Growth Factor-β (TGF-β) signaling in the fruit fly Drosophila melanogaster is activated by nematode infection and certain TGF-β superfamily members regulate the D. melanogaster anti-nematode immune response. Here, we investigate the effect of an entomopathogenic nematode infection factor on host TGF-β pathway regulation and immune function. We find that Heterorhabditis bacteriophora serine carboxypeptidase activates the Activin branch in D. melanogaster adults and the immune deficiency pathway in Activin-deficient flies, it affects hemocyte numbers and survival in flies deficient for Activin signaling, and causes increased intestinal steatosis in Activin-deficient flies. Thus, insights into the D. melanogaster signaling pathways and metabolic processes interacting with H. bacteriophora pathogenicity factors will be applicable to entomopathogenic nematode infection of important agricultural insect pests and vectors of disease.
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LaBonne, C., and M. Whitman. "Mesoderm induction by activin requires FGF-mediated intracellular signals." Development 120, no. 2 (February 1, 1994): 463–72. http://dx.doi.org/10.1242/dev.120.2.463.
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We have examined the role of FGF signaling during activin-mediated mesoderm induction in Xenopus. Using dominant inhibitory mutants of FGF signal transducers to disrupt the FGF-signaling pathway at the plasma membrane or in the cytosol prevents animal cap blastomeres from expressing several mesodermal markers in response to exogenous activin. Dominant inhibitory mutants of the FGF receptor, c-ras or c-raf inhibit the ability of activin to induce molecular markers of both dorsal and ventral mesoderm including Xbra, Mix1 and Xnot. Some transcriptional responses to activin such as goosecoid and Xwnt8 are inhibited less effectively than others, however, suggesting that there may differing requirements for an FGF signal in the responses of mesoderm-specific genes to activin induction. Despite the requirement for this signaling pathway during activin induction, downstream components of this pathway are not activated in response to activin, suggesting that activin does not signal directly through this pathway.
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Lamba, Pankaj, Michelle M. Santos, Daniel P. Philips, and Daniel J. Bernard. "Acute regulation of murine follicle-stimulating hormone β subunit transcription by activin A." Journal of Molecular Endocrinology 36, no. 1 (February 2006): 201–20. http://dx.doi.org/10.1677/jme.1.01961.
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In rodents, activins stimulate immediate-early increases in pituitary follicle-stimulating hormone β (Fshb) subunit transcription. Here, we investigated the underlying signaling mechanisms using the mouse gonadotrope cell line, LβT2. Activin A increased mouse Fshb-luciferase reporter activity within 4 h through a Smad-dependent signaling pathway. The ligand rapidly stimulated formation of SMAD2/3/4 complexes that could interact with a consensus palindromic Smad binding element (SBE) in the proximal Fshb promoter. SMAD over-expression potently stimulated transcription, with the combination of SMADs 2, 3 and 4 producing the greatest synergistic activation. A mutation in the SBE that abolished Smad binding greatly impaired the effects of acute (4 h) activin A treatment and SMAD over-expression on promoter activity, but did not abolish the effects of chronic (24 h) activin A exposure. Within activated SMAD complexes, SMADs 3 and 4 appeared to bind the SBE simultaneously and the binding of both was required for maximal transcriptional activation. Interestingly, the human FSHB promoter, which lacks the consensus SBE, was neither rapidly stimulated by activin A nor by over-expressed SMADs, but was activated by 24 h activin A. Addition of the SBE to the human promoter increased both SMAD2/3/4-sensitivity and acute regulation by activin A, though not to levels observed in mouse. We postulate that short reproductive cycles in female rodents, particularly the brief interval between the primary and secondary FSH surges of the estrous cycle, require the Fshb promoter in these animals to be particularly sensitive to the rapid, Smad-dependent actions of activins on transcription. The human FSHB promoter, in contrast, is chronically regulated by activins seemingly through a SMAD-independent pathway.
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Mwaura, Agnes N., Muhammad A. Riaz, Jane B. Maoga, Ezekiel Mecha, Charles O. A. Omwandho, Georgios Scheiner-Bobis, Ivo Meinhold-Heerlein, and Lutz Konrad. "Activin A Modulates Betaglycan Shedding via the ALK4-SMAD3-Dependent Pathway in Endometriotic Cells." Biomolecules 12, no. 12 (November 24, 2022): 1749. http://dx.doi.org/10.3390/biom12121749.
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The TGF-β superfamily members, activins and inhibins, are mainly involved in cell proliferation, cell survival, invasion, immune surveillance, and lesion growth in endometriosis. Herein, we investigated the modulation of the TGF-β type III receptor (betaglycan or BG) by activin A and inhibin A in endometriosis in vitro. Often, BG undergoes ectodomain shedding releasing soluble BG (sBG) which frequently antagonizes TGF-β signaling. The effects of activin A on BG shedding and signaling pathways involved were evaluated with the inhibitors LY364947 and SIS3, siRNA knockdown in human endometrial cells (12Z, THESC, Ishikawa, and primary stromal cells) and were quantified with BG ELISAs. The effects of activin A and inhibin A on the secretion of MMP2 and MMP3 were analyzed using ELISAs. The effects of activin A on the BG expression were analyzed using RT-qPCR and western blot. The CCK-8 and BrdU assays were used to evaluate the effects of the recombinant BG on cell viability and proliferation. Activin A stimulation resulted in a significant time- and dose-dependent reduction in BG shedding, which was found to be activin A/ALK-4/SMAD3- but not SMAD2-dependent. Activin A increased the BG mRNA expression but had no effect on the protein expression. Likewise, inhibin A was found to block BG shedding. Activin A, but not inhibin A, significantly enhanced the secretion of MMP2 and MMP3. The recombinant BG had no effect on the viability and proliferation of endometriotic cells. Together, these observations support a novel role for activin A with BG in modulating the TGF-β superfamily ligands in endometrial cells in vitro.
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Lanza, Alexis R., and Elaine C. Seaver. "Functional evidence that Activin/Nodal signaling is required for establishing the dorsal-ventral axis in the annelid Capitella teleta." Development 147, no. 18 (September 15, 2020): dev189373. http://dx.doi.org/10.1242/dev.189373.
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ABSTRACTThe TGF-β superfamily comprises two distinct branches: the Activin/Nodal and BMP pathways. During development, signaling by this superfamily regulates a variety of embryological processes, and it has a conserved role in patterning the dorsal-ventral body axis. Recent studies show that BMP signaling establishes the dorsal-ventral axis in some mollusks. However, previous pharmacological inhibition studies in the annelid Capitella teleta, a sister clade to the mollusks, suggests that the dorsal-ventral axis is patterned via Activin/Nodal signaling. Here, we determine the role of both the Activin/Nodal and BMP pathways as they function in Capitella axis patterning. Antisense morpholino oligonucleotides were targeted to Ct-Smad2/3 and Ct-Smad1/5/8, transcription factors specific to the Activin/Nodal and BMP pathways, respectively. Following microinjection of zygotes, resulting morphant larvae were scored for axial anomalies. We demonstrate that the Activin/Nodal pathway of the TGF-β superfamily, but not the BMP pathway, is the primary dorsal-ventral patterning signal in Capitella. These results demonstrate variation in the molecular control of axis patterning across spiralians, despite sharing a conserved cleavage program. We suggest that these findings represent an example of developmental system drift.
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Park, Seung-Won, Chunghee Cho, Byung-Nam Cho, Youngchul Kim, Tae Won Goo, and Young Il Kim. "15-deoxy-Δ12,14-prostaglandin J2Down-Regulates Activin-Induced Activin Receptor, Smad, and Cytokines Expression via Suppression of NF-κB and MAPK Signaling in HepG2 Cells." PPAR Research 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/751261.
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15-Deoxy-Δ12,14-prostaglandin J2(15d-PGJ2) and activin are implicated in the control of apoptosis, cell proliferation, and inflammation in cells. We examined both the mechanism by which 15d-PGJ2regulates the transcription of activin-induced activin receptors (ActR) and Smads in HepG2 cells and the involvement of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in this regulation. Activin A (25 ng/mL) inhibited HepG2 cell proliferation, whereas 15d-PGJ2(2 μM and 5 μM) had no effect. Activin A and 15d-PGJ2showed different regulatory effects on ActR and Smad expression, NF-κB p65 activity and MEK/ERK phosphorylation, whereas they both decreased IL-6 production and increased IL-8 production. When co-stimulated with 15d-PGJ2and activin, 15d-PGJ2inhibited the activin-induced increases in ActR and Smad expression, and decreased activin-induced IL-6 production. However, it increased activin-induced IL-8 production. In addition, 15d-PGJ2inhibited activin-induced NF-κB p65 activity and activin-induced MEK/ERK phosphorylation. These results suggest that 15d-PGJ2suppresses activin-induced ActR and Smad expression, down-regulates IL-6 production, and up-regulates IL-8 production via suppression of NF-κB and MAPK signaling pathway in HepG2 cells. Regulation of ActR and Smad transcript expression and cytokine production involves NF-κB and the MAPK pathway via interaction with 15d-PGJ2/activin/Smad signaling.
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Danila, Daniel C., Xun Zhang, Yunli Zhou, Jaafar N. Sleiman Haidar, and Anne Klibanski. "Overexpression of Wild-Type Activin Receptor Alk4-1 Restores Activin Antiproliferative Effects in Human Pituitary Tumor Cells." Journal of Clinical Endocrinology & Metabolism 87, no. 10 (October 1, 2002): 4741–46. http://dx.doi.org/10.1210/jc.2002-020527.
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Activin is a member of the TGFβ family of cytokines involved in the control of cell proliferation. We have previously shown that the majority of clinically nonfunctioning pituitary tumors do not respond to activin-induced growth suppression. Human pituitary tumors specifically express alternatively spliced activin type I receptor Alk4 mRNAs, producing C-terminus truncated isoforms designated Alk4-2, 4-3, and 4-4. However, it is not known whether these truncated activin receptors suppress activin effects on cell proliferation in human pituitary cells. Therefore, we investigated activin signaling in a human pituitary tumor cell line, HP75, derived from a clinically nonfunctioning pituitary tumor. HP75 cells express activin A mRNA and secrete activin A, as measured by ELISA and a functional bioassay. TGFβ administration decreases the proliferation of HP75 cells, suggesting that the signaling pathway shared by TGFβ and activin is functional in this cell line. However, activin neither inhibits cell proliferation nor stimulates reporter gene expression in HP75 cells, indicating that activin signaling is specifically blocked at the receptor level. HP75 cells express all truncated activin type I receptor Alk4 isoforms, as determined by RT-PCR. Because truncated Alk4 receptor isoforms inhibit activin signaling by competing with the wild-type receptor for binding to activin type II receptors, we hypothesized that overexpression of wild-type activin type I receptor will restore activin signaling. In HP75 cells, cotransfection of the wild-type activin type I receptor Alk4-1 expression vector increases activin-responsive reporter activity. Furthermore, transfection with wild-type activin receptor type I results in activin-mediated suppression of cell proliferation. These data indicate that truncated Alk4 isoforms interfere with activin signaling pathways and thereby may contribute to uncontrolled cell growth. Overexpression of the wild-type Alk4-1 receptor restores responsiveness to activin in human pituitary tumor-derived cells.
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Ryanto, Gusty Rizky Teguh, Ahmad Musthafa, Tetsuya Hara, and Noriaki Emoto. "Inactivating the Uninhibited: The Tale of Activins and Inhibins in Pulmonary Arterial Hypertension." International Journal of Molecular Sciences 24, no. 4 (February 7, 2023): 3332. http://dx.doi.org/10.3390/ijms24043332.
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Advances in technology and biomedical knowledge have led to the effective diagnosis and treatment of an increasing number of rare diseases. Pulmonary arterial hypertension (PAH) is a rare disorder of the pulmonary vasculature that is associated with high mortality and morbidity rates. Although significant progress has been made in understanding PAH and its diagnosis and treatment, numerous unanswered questions remain regarding pulmonary vascular remodeling, a major factor contributing to the increase in pulmonary arterial pressure. Here, we discuss the role of activins and inhibins, both of which belong to the TGF-β superfamily, in PAH development. We examine how these relate to signaling pathways implicated in PAH pathogenesis. Furthermore, we discuss how activin/inhibin-targeting drugs, particularly sotatercep, affect pathophysiology, as these target the afore-mentioned specific pathway. We highlight activin/inhibin signaling as a critical mediator of PAH development that is to be targeted for therapeutic gain, potentially improving patient outcomes in the future.
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Shi, Feng-Tao, Anthony P. Cheung, and Peter C. K. Leung. "Growth Differentiation Factor 9 Enhances Activin A-Induced Inhibin B Production in Human Granulosa Cells." Endocrinology 150, no. 8 (May 7, 2009): 3540–46. http://dx.doi.org/10.1210/en.2009-0267.
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Activin A or growth differentiation factor 9 (GDF9) alone can increase βB-mRNA level in human granulosa-lutein cells from women undergoing in vitro fertilization, but their potential interactions and related cell signaling pathways involved are unknown. We therefore compared inhibin subunit and inhibin levels and activation of activin receptors (ACVRs) and Smad signaling pathway in these human granulosa-lutein cells with and without GDF9 and/or activin A treatment. Inhibin subunit (α, βA, βB), ACVR, and Smad2/3/4/7 mRNA levels, inhibin A and B production, and Smad phosphorylation were assessed by real-time RT-PCR, ELISA, and immunoblotting, respectively. Data were analyzed by ANOVA followed by Tukey’s test. Activin A (1–50 ng/ml) or GDF9 (1–200 ng/ml) alone had only little stimulatory effects on α- and βA-mRNA levels. In contrast, GDF9 could stimulate βB-subunit levels but to a lesser degree than the dose- and time-dependent effects of activin A. Compared with untreated cells, GDF9 pretreatment for 24 h significantly enhanced activin A-induced βB-mRNA levels, inhibin B secretion, and Smad2/3 phosphorylation (effects attenuated by bone morphogenetic protein receptor 2 extracellular domain, a GDF9 antagonist); and induced ACVR2B/1B and Smad2/3 but reduced Smad7 (an inhibitory Smad) mRNA levels. We report here for the first time that GDF9 enhances cell response to activin A by modulating key components of the activin signaling pathway in regulating inhibin subunits and hence inhibin B production in human granulosa-lutein cells.
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Wang, EY, EY Ma, and TK Woodruff. "Activin signal transduction in the fetal rat adrenal gland and in human H295R cells." Journal of Endocrinology 178, no. 1 (July 1, 2003): 137–48. http://dx.doi.org/10.1677/joe.0.1780137.
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The presence of activin A and its effects have previously been documented in the adrenal gland, particularly in the human fetal adrenal gland and the rat adrenal gland. The primary signaling pathway of activin involves interactions between receptor and intracellular (Smad) proteins that have not been completely described in the adrenal gland. In this study, we demonstrate that the components of the activin signaling cascade are present in two complementary models, the fetal rat adrenal gland and the human adrenocortical cell line, H295R, by means of RT-PCR, western analysis, and immunoprecipitation techniques. Using the cell line, activin signaling was analyzed using an activin-responsive reporter gene, p3TP-luc, and luciferase assays to assess transcriptional activity with co-expression of the different activin receptors and Smads to demonstrate the functionality of the signaling cascade. In the fetal rat adrenal gland, the relative amounts of mRNA of the type II receptors, RII and RIIB, were regulated by gestational age, such that the RIIB levels increased after birth while RII levels fell. Using immunodetection techniques, the activin receptors and the different Smad proteins were detected in the rat fetal adrenal glands. Notably, the presence of Smad4 protein is significantly increased after birth in the rat adrenal gland. RT-PCR established a similar profile in the H295R cells. Using p3TP-luc, the H295R cells show transcriptional activation of this activin-responsive reporter in the presence of activin A. Co-expression of type I and type II receptors as well as Smads, results in ligand-independent transcriptional activity in addition to an activin-stimulated response. In determining activin's effects on adrenal function, adrenal steroid production was evaluated by incubation of the H295R cells with increasing doses of activin A and inhibin A, resulting in a detectable increase in P450c17 expression. Co-incubation of activin A with follistatin diminishes this response. These results are consistent with a role for activin A in the adrenal gland by demonstrating that the elements of the activin signaling pathway are present, intact, and functional. This suggests that in the adrenal gland the components of the activin receptor/Smad pathway are dynamically changing in the transition from fetal to neonatal life, and are important to the function of this organ.
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Shi, Ying, Yong Li Bao, Yin Wu, Chun Lei Yu, Yan Xin Huang, Ying Sun, Li Hua Zheng, and Yu Xin Li. "Alantolactone Inhibits Cell Proliferation by Interrupting the Interaction between Cripto-1 and Activin Receptor Type II A in Activin Signaling Pathway." Journal of Biomolecular Screening 16, no. 5 (March 4, 2011): 525–35. http://dx.doi.org/10.1177/1087057111398486.
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It has been suggested that deregulation of activin signaling contributes to tumor formation. Activin signaling is blocked in cancer cells due to the complex formed by Cripto-1, activin, and activin receptor type II (ActRII). In this study, the authors used a mammalian two-hybrid system to construct a drug screening model to obtain a small molecular inhibitor capable of interrupting the interaction between Cripto-1 and ActRII. They screened 300 natural components and identified alantolactone. Data suggested that alantolactone induced activin/SMAD3 signaling in human colon adenocarcinoma HCT-8 cells. The authors also found that alantolactone exhibited antiproliferative function specific to tumor cells, with almost no toxicity to normal cells at a concentration of 5 µg/mL. Furthermore, they proved that the antiproliferative function of alantolactone was activin/SMAD3 dependent. These results suggest that alantolactone performs its antitumor effect by interrupting the interaction between Cripto-1 and the activin receptor type IIA in the activin signaling pathway. Moreover, screening for inhibitors of Cripto-1/ActRII is a potentially beneficial approach to aid in discovering novel cancer treatment.
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Reichelt, Paula, Stephan Bernhart, Franziska Wilke, Sebastian Schwind, Michael Cross, Uwe Platzbecker, and Gerhard Behre. "MicroRNA Expression Patterns Reveal a Role of the TGF-β Family Signaling in AML Chemo-Resistance." Cancers 15, no. 20 (October 21, 2023): 5086. http://dx.doi.org/10.3390/cancers15205086.
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Resistance to chemotherapy is ultimately responsible for the majority of AML-related deaths, making the identification of resistance pathways a high priority. Transcriptomics approaches can be used to identify genes regulated at the level of transcription or mRNA stability but miss microRNA-mediated changes in translation, which are known to play a role in chemo-resistance. To address this, we compared miRNA profiles in paired chemo-sensitive and chemo-resistant subclones of HL60 cells and used a bioinformatics approach to predict affected pathways. From a total of 38 KEGG pathways implicated, TGF-β/activin family signaling was selected for further study. Chemo-resistant HL60 cells showed an increased TGF-β response but were not rendered chemo-sensitive by specific inhibitors. Differential pathway expression in primary AML samples was then investigated at the RNA level using publically available gene expression data in the TGCA database and by longitudinal analysis of pre- and post-resistance samples available from a limited number of patients. This confirmed differential expression and activity of the TGF-β family signaling pathway upon relapse and revealed that the expression of TGF-β and activin signaling genes at diagnosis was associated with overall survival. Our focus on a matched pair of cytarabine sensitive and resistant sublines to identify miRNAs that are associated specifically with resistance, coupled with the use of pathway analysis to rank predicted targets, has thus identified the activin/TGF-β signaling cascade as a potential target for overcoming resistance in AML.
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Besson-Fournier, Celine, Aurelie Gineste, Chloe Latour, Ophelie Gourbeyre, Delphine Meynard, Patricia Aguilar-Martinez, Eric Oswald, Patricia Martin, Helene Coppin, and Marie-Paule Roth. "Hepcidin Upregulation By Inflammation Is Not Causally Related to Liver Activation of Smad1/5/8 Signaling By Activin B." Blood 128, no. 22 (December 2, 2016): 262. http://dx.doi.org/10.1182/blood.v128.22.262.262.
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Abstract Hepcidin induction during inflammation is partly due to direct transcriptional regulation by the IL6/STAT3 pathway. However, SMAD1/5/8 signaling is also believed to have a role in hepcidin regulation during inflammation, as inhibitors of BMP type I receptors or the BMP ligand antagonist ALK3-Fc block hepcidin induction, increase iron availability, and ameliorate anemia in different animal models of inflammation. We previously observed that LPS stimulates liver Smad1/5/8 signaling even in Bmp6-deficient mice and our data suggested that, rather than Bmp6, activin B could be the activating ligand of this pathway during inflammation. There was indeed a dramatic induction of Inhbb mRNA, encoding activin B, in the liver of mice challenged with LPS, slightly preceding an increase in Smad1/5/8 phosphorylation and hepcidin (Hamp) mRNA. In liver cells in vitro, activin B stimulated not only canonical Smad2/3 but also non-canonical Smad1/5/8 signaling and hepcidin expression. Finally, pretreatment with a BMP type I receptor inhibitor showed that the effect of activin B on hepcidin expression in liver cells was entirely attributable to its effect on non-canonical Smad1/5/8 signaling. However, although these data demonstrate that activin B potently crossactivates non-canonical Smad1/5/8 signaling to induce hepcidin expression in hepatocytes in vitro, they do not definitively prove the role of activin B in hepcidin induction in vivo. Therefore, the goal of the present study was to challenge Inhbb-/- mice (deficient in activin B) with LPS or infect them with E. Coli and examine whether, as expected from the in vitro data, the lack of activin B prevents stimulation of both canonical Smad2/3 and non-canonical Smad1/5/8 signaling and induction of hepcidin in these mice. We first showed that activin B is actually the ligand that in vivo induces hepatic Smad2/3 and Smad1/5/8 phosphorylation in response to inflammatory stimuli such as LPS and bacterial infections. Indeed, these signaling pathways are no longer activated in Inhbb-/- mice (Fig. 1A). Interestingly however, we found that the lack of activin B and, as a consequence, the lack of activation of Smad1/5/8 signaling does not impair the induction of hepatic hepcidin expression by these inflammatory stimuli (Fig. 1B), illustrating the limitations of in vitro studies in simulating what is actually going on inside a liver. In conclusion, although activin B is directly responsible for liver activation of Smad1/5/8 signaling in vivo, this signaling pathway is not governing upregulation of hepcidin production in animals submitted to inflammatory stimuli. We also noticed that the level of Smad1/5/8 phosphorylation in the liver of mice challenged with LPS is not correlated with the expression of hepcidin. Indeed, although LPS-treated Bmp6-/- and wild-type mice have similar activation of Smad1/5/8 (Fig. 2A), the amount of circulating hepcidin in Bmp6-/- mice is about three times lower than in wild-type mice (Fig. 2B). This could indicate that induction of Smad1/5/8 signaling by inflammatory stimuli takes place in non-parenchymal cells rather than in hepatocytes and has no impact on hepcidin expression. Further investigations are necessary to determine in which liver cells activin B activates the canonical Smad2/3 and non-canonical Smad1/5/8 signaling observed in this study, and what are the exact target genes induced by this signaling. Disclosures No relevant conflicts of interest to declare.
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Wang, Ying, Catherine C. Ho, EunJin Bang, Carlis A. Rejon, Vanessa Libasci, Pavel Pertchenko, Terence E. Hébert, and Daniel J. Bernard. "Bone Morphogenetic Protein 2 Stimulates Noncanonical SMAD2/3 Signaling via the BMP Type 1A Receptor in Gonadotrope-Like Cells: Implications for FSH Synthesis." Endocrinology 155, no. 5 (May 1, 2014): 1970–81. http://dx.doi.org/10.1210/en.2013-1741.
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FSH is an essential regulator of mammalian reproduction. Its synthesis by pituitary gonadotrope cells is regulated by multiple endocrine and paracrine factors, including TGFβ superfamily ligands, such as the activins and inhibins. Activins stimulate FSH synthesis via transcriptional regulation of its β-subunit gene (Fshb). More recently, bone morphogenetic proteins (BMPs) were shown to stimulate murine Fshb transcription alone and in synergy with activins. BMP2 signals via its canonical type I receptor, BMPR1A (or activin receptor-like kinase 3 [ALK3]), and SMAD1 and SMAD5 to stimulate transcription of inhibitor of DNA binding proteins. Inhibitor of DNA binding proteins then potentiate the actions of activin-stimulated SMAD3 to regulate the Fshb gene in the gonadotrope-like LβT2 cell line. Here, we report the unexpected observation that BMP2 also stimulates the SMAD2/3 pathway in these cells and that it does so directly via ALK3. Indeed, this novel, noncanonical ALK3 activity is completely independent of ALK4, ALK5, and ALK7, the type I receptors most often associated with SMAD2/3 pathway activation. Induction of the SMAD2/3 pathway by ALK3 is dependent upon its own previous activation by associated type II receptors, which phosphorylate conserved serine and threonine residues in the ALK3 juxtamembrane glycine-serine-rich domain. ALK3 signaling via SMAD3 is necessary for the receptor to stimulate Fshb transcription, whereas its activation of the SMAD1/5/8 pathway alone is insufficient. These data challenge current dogma that ALK3 and other BMP type I receptors signal via SMAD1, SMAD5, and SMAD8 and not SMAD2 or SMAD3. Moreover, they suggest that BMPs and activins may use similar intracellular signaling mechanisms to activate the murine Fshb promoter in immortalized gonadotrope-like cells.
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de Guise, Chantal, Annie Lacerte, Shahrzad Rafiei, Rachel Reynaud, Melanie Roy, Thierry Brue, and Jean-Jacques Lebrun. "Activin Inhibits the Human Pit-1 Gene Promoter through the p38 Kinase Pathway in a Smad-Independent Manner." Endocrinology 147, no. 9 (September 1, 2006): 4351–62. http://dx.doi.org/10.1210/en.2006-0444.
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The pituitary transcription factor Pit-1 regulates hormonal production from the anterior pituitary gland. However, the mechanisms by which Pit-1 gene expression is regulated in humans are poorly understood. Activin, a member of the TGFβ superfamily, acts as a negative regulator of cell growth and prolactin gene expression in lactotrope cells. In this study, we show that activin negatively regulates the human Pit-1 gene promoter. We defined a 117-bp element within the Pit-1 promoter that is sufficient to relay these inhibitory effects. We further investigated the signaling pathways that mediate activin-induced inhibition of Pit-1 gene promoter in pituitary lactotrope cells. We found that the activin effects on Pit-1 gene regulation are Smad independent and require the p38 MAPK pathway. Specifically, blocking p38 kinase activity reverses activin-mediated inhibition of the Pit-1 gene promoter. Together, our results highlight the p38 MAPK pathway as a key regulator of activin function in pituitary lactotrope cells and further emphasizes the critical role played by activin in regulating hormonal production in the pituitary gland.
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Deng, Jing, Xin-Xin Guan, Ying-Bao Zhu, Hai-Tao Deng, Guang-Xu Li, Yi-Chen Guo, Peng Jin, Ran-Hui Duan, and Wen Huang. "Reducing the Excess Activin Signaling Rescues Muscle Degeneration in Myotonic Dystrophy Type 2 Drosophila Model." Journal of Personalized Medicine 12, no. 3 (March 2, 2022): 385. http://dx.doi.org/10.3390/jpm12030385.
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Expanded non-coding RNA repeats of CCUG are the underlying genetic causes for myotonic dystrophy type 2 (DM2). There is an urgent need for effective medications and potential drug targets that may alleviate the progression of the disease. In this study, 3140 small-molecule drugs from FDA-approved libraries were screened through lethality and locomotion phenotypes using a DM2 Drosophila model expressing 720 CCTG repeats in the muscle. We identified ten effective drugs that improved survival and locomotor activity of DM2 flies, including four that share the same predicted targets in the TGF-β pathway. The pathway comprises two major branches, the Activin and BMP pathways, which play critical and complex roles in skeletal development, maintenance of homeostasis, and regeneration. The Drosophila model recapitulates pathological features of muscle degeneration in DM2, displaying shortened lifespan, a decline in climbing ability, and progressive muscle degeneration. Increased levels of p-smad3 in response to activin signaling were observed in DM2 flies. Decreased levels of activin signaling using additional specific inhibitors or genetic method ameliorated climbing defects, crushed thoraxes, structure, and organization of muscle fibers. Our results demonstrate that a decrease in activin signaling is sufficient to rescue muscle degeneration and is, therefore, a potential therapeutic target for DM2.
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Walton, Kelly L., Justin L. Chen, Quinn Arnold, Emily Kelly, Mylinh La, Louis Lu, George Lovrecz, et al. "Activin A–Induced Cachectic Wasting Is Attenuated by Systemic Delivery of Its Cognate Propeptide in Male Mice." Endocrinology 160, no. 10 (July 19, 2019): 2417–26. http://dx.doi.org/10.1210/en.2019-00257.
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Abstract In cancer, elevated activin levels promote cachectic wasting of muscle, irrespective of tumor progression. In excess, activins A and B use the myostatin signaling pathway in muscle, triggering a decrease in protein synthesis and an increase in protein degradation, which ultimately leads to atrophy. Recently, we demonstrated that local delivery of engineered activin and myostatin propeptides (natural inhibitors of these growth factors) could induce profound muscle hypertrophy in healthy mice. Additionally, the expression of these propeptides effectively attenuated localized muscle wasting in models of dystrophy and cancer cachexia. In this study, we examined whether a systemically administered recombinant propeptide could reverse activin A–induced cachectic wasting in mice. Chinese hamster ovary cells stably expressing activin A were transplanted into the quadriceps of nude mice and caused an 85-fold increase in circulating activin A levels within 12 days. Elevated activin A induced a rapid reduction in body mass (−16%) and lean mass (−10%). In agreement with previous findings, we demonstrated that adeno-associated virus–mediated delivery of activin propeptide to the tibialis anterior muscle blocked activin-induced wasting. In addition, despite massively elevated levels of activin A in this model, systemic delivery of the propeptide significantly reduced activin-induced changes in lean and body mass. Specifically, recombinant propeptide reversed activin-induced wasting of skeletal muscle, heart, liver, and kidneys. This is the first study to demonstrate that systemic administration of recombinant propeptide therapy effectively attenuates tumor-derived activin A insult in multiple tissues.
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Risbridger, Gail P., Jacqueline F. Schmitt, and David M. Robertson. "Activins and Inhibins in Endocrine and Other Tumors." Endocrine Reviews 22, no. 6 (December 1, 2001): 836–58. http://dx.doi.org/10.1210/edrv.22.6.0450.
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Abstract Inhibin and activin are members of the TGFβ superfamily of growth and differentiation factors. They were first identified as gonadal-derived regulators of pituitary FSH and were subsequently assigned multiple actions in a wide range of tissues. More recently, the inhibin α subunit was considered as a tumor suppressor based on functional studies employing transgenic mouse models. This review evaluates the functional and molecular evidence that the inhibin α subunit is a tumor suppressor in endocrine cancers. The evaluation highlights the discrepant results from the human and mouse studies, as well as the differences between endocrine tumor types. In addition, we examine the evidence that the activin-signaling pathway is tumor suppressive and identify organ-specific differences in the actions and putative roles of this pathway in endocrine tumors. In summary, there is a considerable body of evidence to support the role of inhibins and activins in endocrine-related tumors. Future studies will define the mechanisms by which inhibins and activins contribute to the process of initiation, promotion, or progression of endocrine-related cancers.
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Wiley, Mark B., Jessica Bauer, Kunaal Mehrotra, David N. Church, Rachel S. Kerr, David J. Kerr, Paul Grippo, and Barbara Jung. "Abstract B013: Activin’s influence on the tumor microenvironment in colon cancer." Cancer Research 82, no. 23_Supplement_1 (December 1, 2022): B013. http://dx.doi.org/10.1158/1538-7445.crc22-b013.
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Abstract Background and aims: Activin A (activin) is a key molecule that regulates cell specific and context dependent signaling in tumor growth and metastasis as well as local and systemic inflammatory responses. Understanding the link between tumor-promotive and inflammatory effects may provide a novel opportunity for targeted therapy in colorectal cancer (CRC). We have previously shown that activin signaling promotes epithelial to mesenchymal transition, tumor migration, and that serum activin correlates with advanced stage in CRC patients. Recently, activin has been implicated in enhancing CD4+ to CD8+ communications to promote cytotoxic elimination of tumor cells. We now hypothesize that activin exerts cell-specific effects in the tumor microenvironment (TME) to both promote anti-tumoral activity of immune cells and pro-metastatic behavior of tumor cells in a context-dependent manner. Methods: Western blot and transwell migration assays with and without activin were performed in human epithelial colon cancer cells with varying expression levels of ACVR2 and in human colonic fibroblasts. The influence of the canonical Smad4 pathway was elucidated in a Ts4-Cre;Apcflox;Smad4flox mouse model for CRC. We analyzed a TMA of 1055 stage II and III CRC patients from the QUASAR2 cohort to correlate activin and CD4+ expression with outcome. The TMAs were also analyzed via Digital Spatial Profiling (DSP, NanoString) to determine the immune cell heterogeneity and cell signaling patterns within the tumor microenvironment relative to activin. Results: The non-canonical pAkt pathway is activated in ACVR2-restored but not ACVR2-mutated HCT116+chr2 colon cancer cells, which leads to tumor cell migration in a PI3K-dependent manner. In vivo, ablation of downstream canonical SMAD signaling is associated with elevated activin, alpha-SMA and pAkt and increases in tissue dysplasia, intestinal stromal disorganization, and animal mortality. While there are direct pro-metastatic effects of activin on tumor cells, activin expression in the TME of stage II or III CRC patients is associated with elevated CD4 and survival benefit (High activin/high CD4: 1.665 hazard ratio, 95% Cl of ratio 1.379 to 2.010). DSP analysis confirmed co-localization of activin with immune cells in the TME which influences cell signaling patterns found in these regions. Conclusion: In colon cancer cells, activin leads to preferential prometastatic PI3K/Akt pathway activation. Within the TME, high levels of activin in the presence of CD4+ T-cells is associated with better outcomes in CRC patients. This work lays the foundation to further study context-dependent activin signaling as an adjunct or target in CRC. Citation Format: Mark B. Wiley, Jessica Bauer, Kunaal Mehrotra, David N. Church, Rachel S. Kerr, David J. Kerr, Paul Grippo, Barbara Jung. Activin’s influence on the tumor microenvironment in colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B013.
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Burger, Laura L., Daniel J. Haisenleder, Gordon M. Wotton, Kevin W. Aylor, Alan C. Dalkin, and John C. Marshall. "The regulation of FSHβ transcription by gonadal steroids: testosterone and estradiol modulation of the activin intracellular signaling pathway." American Journal of Physiology-Endocrinology and Metabolism 293, no. 1 (July 2007): E277—E285. http://dx.doi.org/10.1152/ajpendo.00447.2006.
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Recent reports suggest that androgens increase FSHβ transcription directly via the androgen receptor and by modulating activin signaling. Estrogens may also regulate FSHβ transcription in part through the activin system. Activin signaling can be regulated extracellularly via activin, inhibin, or follistatin (FS) or intracellularly via the Smad proteins. We determined the effects of androgen and estrogen on FSHβ primary transcript (PT) concentrations in male and female rats, and we correlated those changes with pituitary: activin βB mRNA, FS mRNA, the mRNAs for Smads2, -3, -4, and -7, and the phosphorylation (p) status of Smad2 and -3 proteins. In males, testosterone (T) increased FSHβ PT two- to threefold between 3 and 24 h and was correlated with reduced FS mRNA, transient increases in Smad2, -4, and -7 mRNAs, and a six- to 10-fold increase in pSmad2, and activin βB mRNA was unchanged. In females, T also increased FSHβ PT twofold and pSmad2 threefold but had no effect on activin βB, FS, or the Smad mRNAs. Androgen also increased Smad2 phosphorylation in gonadotrope-derived αT3 cells. In contrast, estradiol had no effect on FSHβ PT but transiently increased activin βB mRNA and suppressed FS mRNA before increasing FS mRNA at 24 h and increased Smads2, -3, and -7 mRNAs and pSmad2 threefold. In conclusion, T acts on the pituitary to increase FSHβ PT in both sexes and modulates FS mRNA, Smad mRNAs, and/or Smad2 phosphorylation. These findings suggest that T regulates FSHβ transcription, in part, through modulation of various components of the activin-signaling system.
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Shi, Feng-Tao, Anthony P. Cheung, He-Feng Huang, and Peter C. K. Leung. "Effects of Endogenous Growth Differentiation Factor 9 on Activin A-Induced Inhibin B Production in Human Granulosa-Lutein Cells." Journal of Clinical Endocrinology & Metabolism 94, no. 12 (December 1, 2009): 5108–16. http://dx.doi.org/10.1210/jc.2009-1047.
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Background: We recently reported on the effects of exogenous growth differentiation factor 9 (GDF9) in enhancing activin A-induced inhibin βB-subunit mRNA and inhibin B levels in human granulosa-lutein (hGL) cells by modulating key components of the activin signaling pathway. We undertook the following study to characterize the role of endogenous GDF9 in this regard. Methods: We compared inhibin subunit (α, βA, and βB) mRNA and inhibin B levels and activation of activin receptors (ACVRs) and Smad signaling pathway in hGL cells obtained from women undergoing in vitro fertilization and cultured with and without activin A treatment after GDF9-targeting small interfering RNA transfection. GDF9, inhibin subunits, ACVR2B/1B and Smad2/3/4/7 mRNA and/or protein levels, Smad phosphorylation, and inhibin B were assessed with RT-PCR, immunoblotting, and ELISA. Data were analyzed by ANOVA followed by Tukey’s test. Results: GDF9 was detected as mRNA and protein in hGL cells and protein in follicular fluid from all 11 patients tested. Reduced endogenous GDF9 expression after targeting small interfering RNA transfection was associated with decreased ACVR2B/1B and Smad2/3/4 but increased inhibitory Smad7 mRNA and protein levels and, consequently, reduced activin A-induced βB-subunit mRNA and inhibin B levels. Conclusions: We report here for the first time autocrine roles for endogenous GDF9 in hGL cells in enhancing activin A-induced βB-subunit mRNA and inhibin B levels via key components of the activin signaling pathway. However, the relative contributions of GDF9 in granulosa cells vs. oocyte as autocrine/paracrine regulators of βB-subunit and inhibin B production in normal and abnormal human ovarian functions remain to be determined.
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Shi, Feng-Tao, Anthony P. Cheung, He-Feng Huang, and Peter C. K. Leung. "Effects of Endogenous Growth Differentiation Factor 9 on Activin A-Induced Inhibin B Production in Human Granulosa-Lutein Cells." Molecular Endocrinology 23, no. 11 (November 1, 2009): 1936. http://dx.doi.org/10.1210/mend.23.11.9995.
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ABSTRACT Background We recently reported on the effects of exogenous growth differentiation factor 9 (GDF9) in enhancing activin A-induced inhibin βB-subunit mRNA and inhibin B levels in human granulosa-lutein (hGL) cells by modulating key components of the activin signaling pathway. We undertook the following study to characterize the role of endogenous GDF9 in this regard. Methods We compared inhibin subunit (α, βA, and βB) mRNA and inhibin B levels and activation of activin receptors (ACVRs) and Smad signaling pathway in hGL cells obtained from women undergoing in vitro fertilization and cultured with and without activin A treatment after GDF9-targeting small interfering RNA transfection. GDF9, inhibin subunits, ACVR2B/1B and Smad2/3/4/7 mRNA and/or protein levels, Smad phosphorylation, and inhibin B were assessed with RT-PCR, immunoblotting, and ELISA. Data were analyzed by ANOVA followed by Tukey’s test. Results GDF9 was detected as mRNA and protein in hGL cells and protein in follicular fluid from all 11 patients tested. Reduced endogenous GDF9 expression after targeting small interfering RNA transfection was associated with decreased ACVR2B/1B and Smad2/3/4 but increased inhibitory Smad7 mRNA and protein levels and, consequently, reduced activin A-induced βB-subunit mRNA and inhibin B levels. Conclusions We report here for the first time autocrine roles for endogenous GDF9 in hGL cells in enhancing activin A-induced βB-subunit mRNA and inhibin B levels via key components of the activin signaling pathway. However, the relative contributions of GDF9 in granulosa cells vs. oocyte as autocrine/paracrine regulators of βB-subunit and inhibin B production in normal and abnormal human ovarian functions remain to be determined.
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Chen, Wei, Teresa K. Woodruff, and Kelly E. Mayo. "Activin A-Induced HepG2 Liver Cell Apoptosis: Involvement of Activin Receptors and Smad Proteins*." Endocrinology 141, no. 3 (March 1, 2000): 1263–72. http://dx.doi.org/10.1210/endo.141.3.7361.
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Abstract A balance between cell proliferation and apoptosis is important for regulating normal liver function. Proteins of the transforming growth factor-β superfamily are known to be important mediators of apoptosis in the liver. In this study we demonstrate that activin A potently induces apoptotic cell death in a hepatoma cell line, HepG2 cells. To determine the roles of activin receptors and downstream signaling proteins in activin A-induced apoptosis in these cells, the activin signaling pathway was analyzed using the transcription of an activin-responsive reporter gene, p3TP-Lux, as an assay. Although individual activin receptors had little effect on transcriptional activity, coexpression of an activin type I receptor and a type II receptor significantly increased both basal and activin-induced transcriptional activation, with the combination of receptors IB and IIB being the most potent. Similarly, expression of individual Smad proteins had only a modest effect on reporter gene activity, but the combination of Smad2 and Smad4 strongly stimulated transcription. Activin signaling induced a rapid relocation of Smad2 to the nucleus, as determined using a green fluorescence protein-Smad2 fusion protein. In contrast, green fluorescence protein-Smad4 remained localized to the cytoplasm unless it was coexpressed with Smad2. In agreement with the transcriptional response assays, overexpression or suppression of activin signaling components in HepG2 cells altered apoptosis. Overexpression of receptors IB and IIB or Smad proteins 2 and 4 stimulated apoptosis, whereas dominant negative mutant forms of the activin type IIB receptor or Smad2 blocked activin-stimulated apoptosis. These studies suggest that signaling from the cell surface to the nucleus through Smad proteins is a required component of the activin A-induced cell death process in liver cells.
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Lee, Se-Jin, Adam Lehar, Jessica U. Meir, Christina Koch, Andrew Morgan, Lara E. Warren, Renata Rydzik, et al. "Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight." Proceedings of the National Academy of Sciences 117, no. 38 (September 8, 2020): 23942–51. http://dx.doi.org/10.1073/pnas.2014716117.
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Among the physiological consequences of extended spaceflight are loss of skeletal muscle and bone mass. One signaling pathway that plays an important role in maintaining muscle and bone homeostasis is that regulated by the secreted signaling proteins, myostatin (MSTN) and activin A. Here, we used both genetic and pharmacological approaches to investigate the effect of targeting MSTN/activin A signaling in mice that were sent to the International Space Station.Wild typemice lost significant muscle and bone mass during the 33 d spent in microgravity. Muscle weights ofMstn−/−mice, which are about twice those ofwild typemice, were largely maintained during spaceflight. Systemic inhibition of MSTN/activin A signaling using a soluble form of the activin type IIB receptor (ACVR2B), which can bind each of these ligands, led to dramatic increases in both muscle and bone mass, with effects being comparable in ground and flight mice. Exposure to microgravity and treatment with the soluble receptor each led to alterations in numerous signaling pathways, which were reflected in changes in levels of key signaling components in the blood as well as their RNA expression levels in muscle and bone. These findings have implications for therapeutic strategies to combat the concomitant muscle and bone loss occurring in people afflicted with disuse atrophy on Earth as well as in astronauts in space, especially during prolonged missions.
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Morvan, Frederic, Jean-Michel Rondeau, Chao Zou, Giulia Minetti, Clemens Scheufler, Meike Scharenberg, Carsten Jacobi, et al. "Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy." Proceedings of the National Academy of Sciences 114, no. 47 (November 6, 2017): 12448–53. http://dx.doi.org/10.1073/pnas.1707925114.
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The TGF-β family ligands myostatin, GDF11, and activins are negative regulators of skeletal muscle mass, which have been reported to primarily signal via the ActRIIB receptor on skeletal muscle and thereby induce muscle wasting described as cachexia. Use of a soluble ActRIIB-Fc “trap,” to block myostatin pathway signaling in normal or cachectic mice leads to hypertrophy or prevention of muscle loss, perhaps suggesting that the ActRIIB receptor is primarily responsible for muscle growth regulation. Genetic evidence demonstrates however that both ActRIIB- and ActRIIA-deficient mice display a hypertrophic phenotype. Here, we describe the mode of action of bimagrumab (BYM338), as a human dual-specific anti-ActRIIA/ActRIIB antibody, at the molecular and cellular levels. As shown by X-ray analysis, bimagrumab binds to both ActRIIA and ActRIIB ligand binding domains in a competitive manner at the critical myostatin/activin binding site, hence preventing signal transduction through either ActRII. Myostatin and the activins are capable of binding to both ActRIIA and ActRIIB, with different affinities. However, blockade of either single receptor through the use of specific anti-ActRIIA or anti-ActRIIB antibodies achieves only a partial signaling blockade upon myostatin or activin A stimulation, and this leads to only a small increase in muscle mass. Complete neutralization and maximal anabolic response are achieved only by simultaneous blockade of both receptors. These findings demonstrate the importance of ActRIIA in addition to ActRIIB in mediating myostatin and activin signaling and highlight the need for blocking both receptors to achieve a strong functional benefit.
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Liu, Pang-Pin, Hsun-Ming Chang, Jung-Chien Cheng, and Peter C. K. Leung. "Activin A upregulates PTGS2 expression and increases PGE2 production in human granulosa-lutein cells." Reproduction 152, no. 6 (December 2016): 655–64. http://dx.doi.org/10.1530/rep-16-0262.
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Activin A is one of the members of transforming growth factor-β superfamily that is expressed in human large luteal cells, and may act in an autocrine/paracrine manner to regulate luteal function. Prostaglandin-endoperoxide synthase 2 (PTGS2) enzyme and its derivative, prostaglandin E2 (PGE2), play significant roles in the regulation of corpus luteum formation and maintenance. To date, whether activin A can induce the expression of PTGS2 and the production of PGE2 in human granulosa-lutein cells is largely unknown. The aim of this study was to examine the effects of activin A on the regulation of PTGS2 expression and PGE2 production in human granulosa-lutein cells, and to investigate the underlying signal transduction mechanisms. In this study, the immortalized (SVOG cells) and primary human granulosa-lutein cells were used as the cell models. A TGF-β/activin type I receptor inhibitor, SB431542 and small interfering RNAs were used to investigate the activin A-induced downstream signaling pathway. We have demonstrated that activin A upregulated the expression of PTGS2 and increased the production of PGE2 via an ACVR1B-mediated SMAD2/3–SMAD4 signaling pathway. Our results suggest that activin A may be involved in the modulation of human corpus luteum formation via the induction of PTGS2 expression and PGE2 production.
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Looyenga, Brendan D., and Gary D. Hammer. "Genetic Removal of Smad3 from Inhibin-Null Mice Attenuates Tumor Progression by Uncoupling Extracellular Mitogenic Signals from the Cell Cycle Machinery." Molecular Endocrinology 21, no. 10 (October 1, 2007): 2440–57. http://dx.doi.org/10.1210/me.2006-0402.
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Abstract Inhibin and activin are members of the TGFβ family that perform mutually antagonistic signaling roles in the anterior pituitary, gonads, and adrenal gland. Unopposed activin signaling in inhibin-null (Inha−/−) mice causes the formation of granulosa cell tumors in the gonads and adrenal cortex, which depend upon FSH for efficient growth and progression. In this study, we demonstrate that Smad3, a key effector of activin signaling, is expressed at high levels and is constitutively activated in tumors from these mice. Removal of Smad3 from Inha−/− mice by a genetic cross to Smad3-null (Madh3−/−) mice leads to a significant decrease in cyclinD2 expression and a significant attenuation of tumor progression in the gonads and adrenal. The decrease in cyclinD2 levels in compound knockout mice is related to a reduction in mitogenic signaling through the phosphoinositide-3-kinase (PI3-kinase)/Akt pathway, which is required for normal cell cycle progression in tumor cells. Loss of PI3-kinase/Akt signaling cannot be attributed to alterations in IGF expression, suggesting instead that signaling through the FSH receptor is attenuated. Gene expression profiling in the ovaries of Madh3−/− and Inha−/−:Madh3−/− compound knockout mice supports this hypothesis and further suggests that Smad3 is specifically required for FSH to activate PI3-kinase/Akt, but not protein kinase A. Together these observations imply that activin/Smad3 signaling is necessary for efficient signaling by FSH in Inha−/− tumor cells and that interruption of this pathway uncouples FSH from its intracellular mitogenic effectors.
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Wartchow, Krista Minéia, Letícia Rodrigues, Lucas Zingano Suardi, Barbara Carolina Federhen, Nicholas Guerini Selistre, Carlos-Alberto Gonçalves, and Patrícia Sesterheim. "Short-Term Protocols to Obtain Insulin-Producing Cells from Rat Adipose Tissue: Signaling Pathways and In Vivo Effect." International Journal of Molecular Sciences 20, no. 10 (May 18, 2019): 2458. http://dx.doi.org/10.3390/ijms20102458.
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Studies using mesenchymal stromal cells (MSCs) as a source of insulin-secreting cells (IPCs) are a promising path in the pursuit for diabetes therapy. Here, we investigate three short-term differentiation protocols in order to generate IPCs from autologous adipose-derived stromal cells (ADSCs) with an expressive insulin-secreting profile in vitro and in vivo, as well as the signaling pathways involved in the chosen differentiation protocols. We extracted and cultured ADSCs and differentiated them into IPCs, using three different protocols with different inductors. Afterwards, the secretory profile was analyzed and IPCs differentiated in exendin-4/activin A medium, which presented the best secretory profile, was implanted in the kidney subcapsular region of diabetic rats. All protocols induced the differentiation, but media supplemented with exendin-4/activin A or resveratrol induced the expression and secretion of insulin more efficiently, and only the exendin-4/activin-A-supplemented medium generated an insulin secretion profile more like β-cells, in response to glucose. The PI3K/Akt pathway seems to play a negative role in IPC differentiation; however, the differentiation of ADSCs with exendin-4/activin A positively modulated the p38/MAPK pathway. Resveratrol medium activated the Jak/STAT3 pathway and generated IPCs apparently less sensitive to insulin and insulin-like receptors. Finally, the implant of IPCs with the best secretory behavior caused a decrease in hyperglycemia after one-week implantation in diabetic rats. Our data provide further information regarding the generation of IPCs from ADSCs and strengthen evidence to support the use of MSCs in regenerative medicine, specially the use of exendin-4/activin A to produce rapid and effectively IPCs with significant in vivo effects.
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Luckett, Kathleen A., Jennifer R. Cracchiolo, Gnana P. Krishnamoorthy, Luis Javier Leandro-Garcia, James Nagarajah, Mahesh Saqcena, Rona Lester, et al. "Co-inhibition of SMAD and MAPK signaling enhances 124I uptake in BRAF-mutant thyroid cancers." Endocrine-Related Cancer 28, no. 6 (June 1, 2021): 391–402. http://dx.doi.org/10.1530/erc-21-0017.
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Constitutive MAPK activation silences genes required for iodide uptake and thyroid hormone biosynthesis in thyroid follicular cells. Accordingly, most BRAFV600E papillary thyroid cancers (PTC) are refractory to radioiodide (RAI) therapy. MAPK pathway inhibitors rescue thyroid-differentiated properties and RAI responsiveness in mice and patient subsets with BRAFV600E-mutant PTC. TGFB1 also impairs thyroid differentiation and has been proposed to mediate the effects of mutant BRAF. We generated a mouse model of BRAFV600E-PTC with thyroid-specific knockout of the Tgfbr1 gene to investigate the role of TGFB1 on thyroid-differentiated gene expression and RAI uptake in vivo. Despite appropriate loss of Tgfbr1, pSMAD levels remained high, indicating that ligands other than TGFB1 were engaging in this pathway. The activin ligand subunits Inhba and Inhbb were found to be overexpressed in BRAFV600E-mutant thyroid cancers. Treatment with follistatin, a potent inhibitor of activin, or vactosertib, which inhibits both TGFBR1 and the activin type I receptor ALK4, induced a profound inhibition of pSMAD in BRAFV600E-PTCs. Blocking SMAD signaling alone was insufficient to enhance iodide uptake in the setting of constitutive MAPK activation. However, combination treatment with either follistatin or vactosertib and the MEK inhibitor CKI increased 124I uptake compared to CKI alone. In summary, activin family ligands converge to induce pSMAD in Braf-mutant PTCs. Dedifferentiation of BRAFV600E-PTCs cannot be ascribed primarily to activation of SMAD. However, targeting TGFβ/activin-induced pSMAD augmented MAPK inhibitor effects on iodine incorporation into BRAF tumor cells, indicating that these two pathways exert interdependent effects on the differentiation state of thyroid cancer cells.
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Horvath, Lukas, Daniel Bodmer, Vesna Radojevic, and Arianne Monge Naldi. "Activin Signaling Disruption in the Cochlea Does Not Influence Hearing in Adult Mice." Audiology and Neurotology 20, no. 1 (November 26, 2014): 51–61. http://dx.doi.org/10.1159/000366152.
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Activin, a member of the TGF-F superfamily, was found to play an important role in the development, repair and apoptosis of different tissues and organs. Accordingly, activin signaling is involved in the development of the cochlea. Activin binds to its receptor ActRII, then dimerizes with ActRI and induces a signaling pathway resulting in gene expression. A study reported a case of fibrodysplasia ossificans progressiva with an unusual mutation in the ActRI gene leading to sensorineural hearing loss. This draws attention to the role of activin and its receptors in the developed cochlea. To date, only the expression of ActRII is known in the adult mammalian cochlea. In this study, we present for the first time the presence of activin A and ActRIB in the adult cochlea. Transgenic mice with postnatal dominant-negative ActRIB expression causing disruption of activin signaling in vivo were used for assessing cochlear morphology and hearing ability through the auditory brainstem response (ABR) threshold. Nonfunctioning ActRIB did not affect the ABR thresholds and did not alter the microscopic anatomy of the cochlea. We conclude, therefore, that activin signaling is not necessary for hearing in adult mice under physiological conditions but may be important during and after damaging events in the inner ear. i 2014 S. Karger AG, Basel
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Vallet, Sonia, Siddhartha Mukherjee, Nileshwari Vaghela, Teru Hideshima, Mariateresa Fulciniti, Samantha Pozzi, Loredana Santo, et al. "Molecular Sequaele of Activin A-Dependent Osteoblast Inhibition in Myeloma." Blood 114, no. 22 (November 20, 2009): 1789. http://dx.doi.org/10.1182/blood.v114.22.1789.1789.
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Abstract Abstract 1789 Poster Board I-815 Understanding the pathogenesis of cancer-related bone disease is critical to the discovery of new therapies. The development of osteolytic lesions in multiple myeloma (MM) results from unopposed osteoclast activity due to decreased osteoblast (OB) function. We recently demonstrated that activin A contributes to MM-mediated OB inhibition. The availability of a clinical-grade activin A inhibitor that reduces tumor burden by restoring the bone structure in vivo, underscores the relevance of this pathway in the development of MM-bone disease. Here, we characterize the signaling pathway mediating OB inhibition by activin A. Activin A secretion by bone marrow stromal cells (BMSC) is enhanced in the presence of MM cells which was completely abrogated and using a transwell system. To identify the receptors and pathways involved in activin A secretion, we used neutralizing antibody against several integrins, CD40 and osteopontin. Only VLA4 neutralizing antibodies partially inhibited activin secretion by about 20% (range 10-30%, p<0.05). Since activin A promoter contains a cJUN-binding sequence, we explored the relations between JNK and activin. We show that upon MM cell binding to BMSC, stromal-derived JNK is phosphorylated and SP600125 (20 μM), a specific JNK inhibitor, impairs activin A secretion by BMSC both at basal conditions and in the presence of MM (40% and 54%, respectively; p<0.01). These results suggest that activin secretion requires JNK activation induced by cell-to-cell contact. We next investigated the mechanism underlying activin-mediated OB inhibition by assessing the activity of several signaling pathways critical to OB differentiation. First, we showed that activin A induces SMAD2 phosphorylation, while no effects were noted on SMAD1, β-catenin, pP65 and pERK. Then, using a doxycycline-inducible β-catenin system, we demonstrate that β-catenin activation overcomes activin A inhibition of OB differentiation. These results suggest that activin/SMAD2 and β-catenin modulate OB differentiation by affecting a common downstream target. We next evaluated the expression of two candidates, the transcription factors RUNX2 and DLX5. Only DLX5 expression was downregulated by exogenous activin A (5 fold decrease at 96 hours, p< 0.01). Specific inhibition of SMAD2 via shRNA-mediated knock-down upregulated basal DLX5 and ALP mRNA expression (1.5 and 4.7 fold increase respectively, p<0.05), and partially overcame activin A inhibitory effects. In turn, DLX5 knock-down abrogated OB differentiation without additive effects by exogenous activin A. The clinical relevance of DLX5 was confirmed by the strong correlation between its expression levels in BM biopsies from MM patients and activin A levels in BM serum. Finally, we demonstrate by in vitro and in-vivo studies that MM-mediated DLX5 inhibition is restored by treatment with RAP-011, the specific activin inhibitor. In conclusion, we show that MM cell engagement of BMSC enhances activin A secretion via adhesion-mediated JNK activation and activin A, in turn, inhibits osteoblast differentiation via SMAD2-dependent DLX5 downregulation. This study identifies a novel pathway relevant to OB differentiation and amenable to drug targeting. Disclosures Chauhan: Nereus Pharmaceuticals, Inc: Consultancy. Seehra:Acceleron Pharma: Employment. Anderson:Celgene : Research Funding; Novartis: Research Funding; Millennium: Research Funding. Scadden:Fate Therapeutics: Consultancy. Raje:Astrazeneca, Novartis, Celgene: Research Funding.
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Demir, Ferda, Kyoji Urayama, Anais Audebrand, Ayca Toprak-Semiz, Marja Steenman, Hitoshi Kurose, and Canan G. Nebigil. "Pressure Overload–Mediated Sustained PKR2 (Prokineticin-2 Receptor) Signaling in Cardiomyocytes Contributes to Cardiac Hypertrophy and Endotheliopathies." Hypertension 77, no. 5 (May 2021): 1559–70. http://dx.doi.org/10.1161/hypertensionaha.120.16808.
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Chronic cardiac pressure overload, caused by conditions, such as hypertension, induces pathological hypertrophic growth of myocardium and vascular rarefaction, with largely unknown mechanisms. Here, we described that expression of the PKR2 (prokineticin-2 receptor) is increased in the cardiomyocytes of mice following transaortic constriction pressure overload–mediated pathological hypertrophy. To identify PKR2-induced pathways, we performed microarray analysis on TG-PKR2 (transgenic mice overexpressing cardiomyocyte-restricted human PKR2) hearts and cytokine analyses in hPKR2 overexpressing H9c2-lines (PKR2-cardiomyocytes). An enrichment of activin pathway gene sets was found in both TG-PKR2 and transaortic constriction-operated hearts. Elevated levels of 2 cytokines activin A and its coreceptor, sENG (soluble Endoglin), were found in both PKR2-cardiomyocytes and in PKR2-cardiomyocytes conditioned medium. ELISA analyses of the cardiomyocytes derived from both TG-PKR2 and transaortic constriction hearts revealed high levels of these cardiokines that were repressed with antibodies blocking PKR2, indicating a PKR2-dependent event. The conditioned medium of PKR2-cardiomyocytes induced fenestration of endothelial cells and inhibited tube-like formations. These endotheliopathies were blocked by either depleting activin A or sENG from conditioned medium or by using 2 pharmacological inhibitors, follistatin, and TRC105. In addition, similar endotheliopathies were produced by exogenous administration of activin A and ENG. Prolonged exposure to prokineticin-2 in PKR2-cardiomyocytes increased cell volume by the PKR2/Gα 12/13 /ERK5-pathway. Activation of the PKR2/Gα 12/13 /matrix metalloprotease-pathway promoted both activin A and sENG release. This study reveals that pressure overload–mediated PKR2 signaling in cardiomyocytes contributes to cardiac hypertrophy through autocrine signaling, and vascular rarefaction via cardiac cytokine-mediated cardiomyocyte–endothelial cell communications. Our results may contribute to the development of potential therapeutic targets for heart failure.
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Jeanpierre, Sandrine, Franck Emmanuel Nicolini, Bastien Kaniewski, Charles Dumontet, Ruth Rimokh, Alain Puisieux, and Véronique Maguer-Satta. "BMP4 regulation of human megakaryocytic differentiation is involved in thrombopoietin signaling." Blood 112, no. 8 (October 15, 2008): 3154–63. http://dx.doi.org/10.1182/blood-2008-03-145326.
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Abstract Activin A, BMP2, and BMP4, 3 members of the transforming growth factor-β family, are involved in the regulation of hematopoiesis. Here, we explored the role of these molecules in human megakaryopoiesis using an in vitro serum-free assay. Our results highlight for the first time that, in the absence of thrombopoietin, BMP4 is able to induce CD34+ progenitor differentiation into megakaryocytes through all stages. Although we have previously shown that activin A and BMP2 are involved in erythropoietic commitment, these molecules have no effect on human megakaryopoietic engagement and differentiation. Using signaling pathway-specific inhibitors, we show that BMP4, like thrombopoietin, exerts its effects on human megakaryopoiesis through the JAK/STAT and mTor pathways. Inhibition of the BMP signaling pathway with blocking antibodies, natural soluble inhibitors (FLRG or follistatin), or soluble BMP receptors reveals that thrombopoietin uses the BMP4 pathway to induce megakaryopoiesis, whereas the inverse is not occurring. Finally, we show that thrombopoietin up-regulates the BMP4 autocrine loop in megakaryocytic progenitors by inducing their production of BMP4 and up-regulating BMP receptor expression. In summary, this work indicates that BMP4 plays an important role in the control of human megakaryopoiesis.
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Lee, Michelle A., Janet Heasman, and Malcolm Whitman. "Timing of endogenous activin-like signals and regional specification of theXenopusembryo." Development 128, no. 15 (August 1, 2001): 2939–52. http://dx.doi.org/10.1242/dev.128.15.2939.
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Signaling by activin-like ligands is important for induction and patterning of mesoderm and endoderm. We have used an antibody that specifically recognizes the phosphorylated and activated form of Smad2, an intracellular transducer of activin-like ligands, to examine how this signaling pathway patterns the early mesendoderm. In contrast to the simple expectation that activin-like signaling should be highest on the dorsal side of the gastrula stage embryo, we have found that while Smad2 phosphorylation is highest dorsally before gastrulation, signaling is attenuated dorsally and is highest on the ventral side by mid-gastrulation. Early dorsal initiation of Smad2 phosphorylation results from cooperation between the vegetally localized maternal transcription factor VegT and dorsally localized β-catenin. The subsequent ventral appearance of Smad2 phosphorylation is dependent on VegT, but not on signaling from the dorsal side. Dorsal attenuation of Smad2 phosphorylation during gastrulation is mediated by early dorsal expression of feedback inhibitors of activin-like signals.In addition to regulation of Smad2 phosphorylation by the expression of activin-like ligands and their antagonists, the responsiveness of embryonic cells to activin-like ligands is also temporally regulated. Ectopic Vg1, Xnr1 and derrière all fail to activate Smad2 phosphorylation until after the midblastula transition, and the onset of responsiveness to these ligands is independent of transcription. Furthermore, the timing of cellular responsiveness differs for Xnr1 and derrière, and these distinct temporal patterns of responsiveness can be correlated with their distinctive phenotypic effects. These observations suggest that the timing of endogenous activin-like signaling is a determinant of patterning in the early Xenopus embryo.
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Besson-Fournier, Céline, Chloé Latour, Léon Kautz, Jessica Bertrand, Tomas Ganz, Marie-Paule Roth, and Hélène Coppin. "Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling." Blood 120, no. 2 (July 12, 2012): 431–39. http://dx.doi.org/10.1182/blood-2012-02-411470.
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Abstract Anemia is very common in patients suffering from infections or chronic inflammation and can add substantially to the morbidity of the underlying disease. It is mediated by excessive production of the iron-regulatory peptide hepcidin, but the signaling pathway responsible for hepcidin up-regulation in the inflammatory context is still not understood completely. In the present study, we show that activin B has an unexpected but crucial role in the induction of hepcidin by inflammation. There is a dramatic induction of Inhbb mRNA, encoding the activin βB-subunit, in the livers of mice challenged with lipopolysaccharide, slightly preceding an increase in Smad1/5/8 phosphorylation and Hamp mRNA. Activin B also induces Smad1/5/8 phosphorylation in human hepatoma–derived cells and, synergistically with IL-6 and STAT-3 signaling, up-regulates hepcidin expression markedly, an observation confirmed in mouse primary hepatocytes. Pretreatment with a bone morphogenic protein type I receptor inhibitor showed that the effect of activin B on hepcidin expression is entirely attributable to its effect on bone morphogenetic protein signaling, most likely via activin receptor-like kinase 3. Activin B is therefore a novel and specific target for the treatment of anemia of inflammation.
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Wiley, Mark B., Jessica Bauer, Kunaal Mehrotra, Jasmin Zessner-Spitzenberg, Zoe Kolics, Wenxuan Cheng, Karla Castellanos, et al. "Non-Canonical Activin A Signaling Stimulates Context-Dependent and Cellular-Specific Outcomes in CRC to Promote Tumor Cell Migration and Immune Tolerance." Cancers 15, no. 11 (May 31, 2023): 3003. http://dx.doi.org/10.3390/cancers15113003.
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We have shown that activin A (activin), a TGF-β superfamily member, has pro-metastatic effects in colorectal cancer (CRC). In lung cancer, activin activates pro-metastatic pathways to enhance tumor cell survival and migration while augmenting CD4+ to CD8+ communications to promote cytotoxicity. Here, we hypothesized that activin exerts cell-specific effects in the tumor microenvironment (TME) of CRC to promote anti-tumoral activity of immune cells and the pro-metastatic behavior of tumor cells in a cell-specific and context-dependent manner. We generated an Smad4 epithelial cell specific knockout (Smad4−/−) which was crossed with TS4-Cre mice to identify SMAD-specific changes in CRC. We also performed IHC and digital spatial profiling (DSP) of tissue microarrays (TMAs) obtained from 1055 stage II and III CRC patients in the QUASAR 2 clinical trial. We transfected the CRC cells to reduce their activin production and injected them into mice with intermittent tumor measurements to determine how cancer-derived activin alters tumor growth in vivo. In vivo, Smad4−/− mice displayed elevated colonic activin and pAKT expression and increased mortality. IHC analysis of the TMA samples revealed increased activin was required for TGF-β-associated improved outcomes in CRC. DSP analysis identified that activin co-localization in the stroma was coupled with increases in T-cell exhaustion markers, activation markers of antigen presenting cells (APCs), and effectors of the PI3K/AKT pathway. Activin-stimulated PI3K-dependent CRC transwell migration, and the in vivo loss of activin lead to smaller CRC tumors. Taken together, activin is a targetable, highly context-dependent molecule with effects on CRC growth, migration, and TME immune plasticity.
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Patrnogic, Jelena, Christa Heryanto, and Ioannis Eleftherianos. "Transcriptional up-regulation of the TGF-β intracellular signaling transducer Mad of Drosophila larvae in response to parasitic nematode infection." Innate Immunity 24, no. 6 (July 26, 2018): 349–56. http://dx.doi.org/10.1177/1753425918790663.
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The common fruit fly Drosophila melanogaster is an exceptional model for dissecting innate immunity. However, our knowledge on responses to parasitic nematode infections still lags behind. Recent studies have demonstrated that the well-conserved TGF-β signaling pathway participates in immune processes of the fly, including the anti-nematode response. To elucidate the molecular basis of TGF-β anti-nematode activity, we performed a transcript level analysis of different TGF-β signaling components following infection of D. melanogaster larvae with the nematode parasite Heterorhabditis gerrardi. We found no significant changes in the transcript level of most extracellular ligands in both bone morphogenic protein (BMP) and activin branches of the TGF-β signaling pathway between nematode-infected larvae and uninfected controls. However, extracellular ligand, Scw, and Type I receptor, Sax, in the BMP pathway as well as the Type I receptor, Babo, in the activin pathway were substantially up-regulated following H. gerrardi infection. Our results suggest that receptor up-regulation leads to transcriptional up-regulation of the intracellular component Mad in response to H. gerrardi following changes in gene expression of intracellular receptors of both TGF-β signaling branches. These findings identify the involvement of certain TGF-β signaling pathway components in the immune signal transduction of D. melanogaster larvae against parasitic nematodes .
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Do, Thuy-Vy, Lena A. Kubba, Monica Antenos, Alfred W. Rademaker, Charles D. Sturgis, and Teresa K. Woodruff. "The Role of Activin A and Akt/GSK Signaling in Ovarian Tumor Biology." Endocrinology 149, no. 8 (May 1, 2008): 3809–16. http://dx.doi.org/10.1210/en.2007-1584.
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Elevated activin A levels in serum, cyst fluid, and peritoneal fluid of ovarian cancer patients suggest a role for this peptide hormone in disease development. We hypothesize that activin A plays a role in ovarian tumor biology, and analyzed activin-mediated pro-oncogenic signaling in vitro and the expression of activin signaling pathway molecules in vivo. Activin A regulation of Akt and GSK, and the effects of repressing the activities of these molecules (with pharmacological inhibitors) on cellular proliferation were assessed in the cell line, OVCA429. Activin A activated Akt, which phosphorylated GSK, repressing GSK activity in vitro. Activin A stimulated cellular proliferation and repression of GSK augmented activin-regulated proliferation. To validate in vitro observations, immunostaining of the βA-subunit of activin A and phospho-GSKα/β (Ser9/21) was performed, and the correlation between immunoreactivity levels of these markers and survival was evaluated in benign serous cystadenoma, borderline tumor, and cystadenocarcinoma microarrays. Analysis of tissue microarrays revealed that βA expression in epithelia did not correlate with survival or malignancy, but expression was elevated in stromal cells from carcinomas when compared with benign tumors. Phospho-GSKα/β (Ser9/21) staining was more intense in mitotically active carcinoma cells and exhibited a polarized localization in benign neoplasms that was absent in carcinomas. Notably, lower phospho-GSKα/β (Ser9/21) immunoreactivity correlated with better survival for carcinoma patients (P = 0.046). Our data are consistent with a model in which activin A may mediate ovarian oncogenesis by activating Akt and repressing GSK to stimulate cellular proliferation.
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Osada, S. I., and C. V. Wright. "Xenopus nodal-related signaling is essential for mesendodermal patterning during early embryogenesis." Development 126, no. 14 (July 15, 1999): 3229–40. http://dx.doi.org/10.1242/dev.126.14.3229.
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Previously, we showed that Xenopus nodal-related factors (Xnrs) can act as mesoderm inducers, and that activin induces Xnr transcription, suggesting that Xnrs relay or maintain induction processes initiated by activin-like molecules. We used a dominant negative cleavage mutant Xnr2 (cmXnr2) to carry out loss-of-function experiments to explore the requirement for Xnr signaling in early amphibian embryogenesis, and the relationship between activin and Xnrs. cmXnr2 blocked mesoderm induction caused by Xnr, but not activin, RNA. In contrast, cmXnr2 did suppress mesoderm and endoderm induction by activin protein, while Xnr transcript induction was unaffected by cmXnr2, consistent with an interference with the function of Xnr peptides that were induced by activin protein treatment. The severe hyperdorsalization and gastrulation defects caused by Xnr2 in whole embryos were rescued by cmXnr2, establishing a specific antagonistic relationship between the normal and cleavage mutant proteins. Expression of cmXnr2 resulted in delayed dorsal lip formation and a range of anterior truncations that were associated with delayed and suppressed expression of markers for dorsoanterior endoderm, in which the recently recognized head organizer activity resides. Reciprocally, Xnr2 induced dorsoanterior endodermal markers, such as cerberus, Xhex-1 and Frzb, in animal cap ectoderm. The migratory behavior of head mesendoderm explanted from cmXnr2 RNA-injected embryos was drastically reduced. These results indicate that Xnrs play crucial roles in initiating gastrulation, probably by acting downstream of an activin-like signaling pathway that leads to dorsal mesendodermal specification, including setting up the head organizer.
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Suszko, Magdalena I., Denise J. Lo, Hoonkyo Suh, Sally A. Camper, and Teresa K. Woodruff. "Regulation of the Rat Follicle-Stimulating Hormone β-Subunit Promoter by Activin." Molecular Endocrinology 17, no. 3 (March 1, 2003): 318–32. http://dx.doi.org/10.1210/me.2002-0081.
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Abstract FSH is controlled by a variety of positive and negative stimuli, and the unique FSHβ-subunit is a major target for this regulation. Activin is a key modulator of FSHβ transcription and hormone secretion. The signal transduction pathway leading to FSH expression was previously unknown. Here, we show that the transcription factors Smad3 and Smad4 mediate activin-stimulated activity of the rat FSHβ promoter in a pituitary-derived cell line, LβT2. Cells were transiently transfected with the rat FSHβ promoter fused to a luciferase reporter gene (−338rFSHβ-Luc), and a minimal activin-responsive region was identified. Transfection of Smad3, but not the highly related Smad2, led to a ligand-independent stimulation of the FSHβ promoter activity. As expected, activin caused an additional increase of luciferase expression, which was blocked by cotreatment with follistatin. Although Smad4 alone had no effect on FSHβ transcription, it significantly augmented Smad3 and activin-mediated stimulation of the promoter. A palindromic consensus Smad-binding element in the proximal promoter was found to bind Smad4, and elimination of the region resulted in a loss of activin-mediated FSHβ transcription. The activin signaling pathway is conserved in a number of cells, but FSHβ expression is restricted to gonadotropes. A pituitary-specific transcription factor necessary for activin-dependent induction of the FSHβ promoter has been identified that permits FSHβ expression in nongonadotrope cells. Pitx2 is a member of Pitx subfamily of bicoid-related homeodomain factors that is required for pituitary development and is present in the adult pituitary. This factor was transfected into LβT2 cells, where it caused up-regulation of basal and activin-mediated FSHβ promoter activity. Furthermore, cotransfection of Pitx2c with Smad3 in kidney-derived TSA cells resulted in activin-regulated FSHβ response, suggesting its important role in tissue-restricted regulation of FSHβ by activin. A Pitx2c binding site was identified within the proximal promoter, and elimination of this region also resulted in a loss of activin-regulated FSHβ promoter activity. Taken together, these studies suggest that the regulation of FSHβ is dependent on activin-mediated signaling factors in concert with pituitary-derived nuclear regulatory proteins.
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Moody, Sarah C., Shoichi Wakitani, Julia C. Young, Patrick S. Western, and Kate L. Loveland. "Evidence that activin A directly modulates early human male germline differentiation status." Reproduction 160, no. 1 (July 2020): 141–54. http://dx.doi.org/10.1530/rep-20-0095.
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Disrupted fetal germline development underpins testicular germ cell neoplasia, which is increasing worldwide. The complex signaling milieu during normal testis development includes TGFβ superfamily ligands; this study tests the hypothesis that, activin A, a TGFβ superfamily member, can influence gonocyte development. The human seminoma-derived cell line, TCam-2, a model of fetal gonocytes, was cultured with activin A (1.25–25 ng/mL) for 48 h, or with 5 ng/mL activin A for short- (6, 24, and 48 h) and long-term (13 days) exposures, and downstream targets measured by qRT-PCR. Transcripts that exhibited significant dose-dependent responses to activin A included the early germ cell markers KIT, NODAL, and CRIPTO (NODALl co-receptor and activin inhibitor) which all increased and the differentiation marker DNMT3L which decreased. After 48 h, KIT, NODAL, and CRIPTO levels were significantly higher, while the differentiation marker NANOS2 was significantly lower. Interestingly, activin A exposure also significantly reduced both transcript and protein levels of the PIWI/piRNA pathway component DNMT3L. Because TCam-2 cells produce the activin inhibitor CRIPTO, CRIPTO was reduced using siRNA prior to activin A exposure. This selectively increased KIT in response to activin A. Other ligands present in the fetal testis (BMP4, FGF9, TGFβ1, and TGFβ2) induced distinct effects on germline marker expression. This study showed that activin A can directly modulate germline markers in this human gonocyte-like cell, promoting a less-differentiated phenotype. Additional findings indicate evidence of signaling crosstalk between activin A and NODAL, leading to target-specific effects on gonocyte differentiation.
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Schoenmaker, Ton, Michal Mokry, Dimitra Micha, Coen Netelenbos, Nathalie Bravenboer, Marjolijn Gilijamse, E. Marelise W. Eekhoff, and Teun J. de Vries. "Activin-A Induces Early Differential Gene Expression Exclusively in Periodontal Ligament Fibroblasts from Fibrodysplasia Ossificans Progressiva Patients." Biomedicines 9, no. 6 (June 1, 2021): 629. http://dx.doi.org/10.3390/biomedicines9060629.
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Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease characterized by heterotopic ossification (HO). It is caused by mutations in the Activin receptor type 1 (ACVR1) gene, resulting in enhanced responsiveness to ligands, specifically to Activin-A. Though it has been shown that capturing Activin-A protects against heterotopic ossification in animal models, the exact underlying mechanisms at the gene expression level causing ACVR1 R206H-mediated ossifications and progression are thus far unknown. We investigated the early transcriptomic changes induced by Activin-A of healthy control and patient-derived periodontal ligament fibroblasts (PLF) isolated from extracted teeth by RNA sequencing analysis. To study early differences in response to Activin-A, periodontal ligament fibroblasts from six control teeth and from six FOP patient teeth were cultured for 24 h without and with 50 ng/mL Activin-A and analyzed with RNA sequencing. Pathway analysis on genes upregulated by Activin-A in FOP cells showed an association with pathways involved in, among others, Activin, TGFβ, and BMP signaling. Differential gene expression induced by Activin-A was exclusively seen in the FOP cells. Median centered supervised gene expression analysis showed distinct clusters of up- and downregulated genes in the FOP cultures after stimulation with Activin-A. The upregulated genes with high fold changes like SHOC2, TTC1, PAPSS2, DOCK7, and LOX are all associated with bone metabolism. Our open-ended approach to investigating the early effect of Activin-A on gene expression in control and FOP PLF shows that the molecule exclusively induces differential gene expression in FOP cells and not in control cells.
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Cocolakis, Eftihia, Meiou Dai, Loren Drevet, Joanne Ho, Eric Haines, Suhad Ali, and Jean-Jacques Lebrun. "Smad Signaling Antagonizes STAT5-mediated Gene Transcription and Mammary Epithelial Cell Differentiation." Journal of Biological Chemistry 283, no. 3 (November 17, 2007): 1293–307. http://dx.doi.org/10.1074/jbc.m707492200.
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Both the transforming growth factor-β (TGFβ)/Smad and the prolactin/JAK/STAT pathway are critical to the proper development, maintenance, and function of the mammary epithelial tissue. Interestingly, opposing physiological effects between these two signaling pathways are prominent in the regulation of mammary gland development. However, the exact nature of the biological network existing between the Smad and STAT signal transduction pathways has remained elusive. We identified a novel regulatory cross-talk mechanism by which TGFβ-induced Smad signaling acts to antagonize prolactin-mediated JAK/STAT signaling and expression of target genes. Furthermore, we found activin, another member of the TGFβ family, to also efficiently block STAT5 signaling and β-casein expression in mammary epithelial cells. Our results indicate that ligand-induced activation of Smad2, -3, and -4 by activin and TGFβ leads to a direct inhibition of STAT5 transactivation and STAT5-mediated transcription of the downstream target genes, β-casein and cyclin D1, thereby blocking vital processes for mammary gland growth and differentiation. Finally, we unveiled the mechanism by which these two signaling cascades antagonize their effects, and we found that activated Smads inhibit STAT5 association with its co-activator CREB-binding protein, thus blocking STAT5 transactivation of its target genes and leading to inhibition of mammary gland differentiation and lactation.