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1
Maciaszczyk-Dziubinska, Ewa, Anna Reymer, Nallani Vijay Kumar, et al. "The ancillary N-terminal region of the yeast AP-1 transcription factor Yap8 contributes to its DNA binding specificity." Nucleic Acids Research 48, no. 10 (2020): 5426–41. http://dx.doi.org/10.1093/nar/gkaa316.
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Abstract Activator protein 1 (AP-1) is one of the largest families of basic leucine zipper (bZIP) transcription factors in eukaryotic cells. How AP-1 proteins achieve target DNA binding specificity remains elusive. In Saccharomyces cerevisiae, the AP-1-like protein (Yap) family comprises eight members (Yap1 to Yap8) that display distinct genomic target sites despite high sequence homology of their DNA binding bZIP domains. In contrast to the other members of the Yap family, which preferentially bind to short (7–8 bp) DNA motifs, Yap8 binds to an unusually long DNA motif (13 bp). It has been unclear what determines this unique specificity of Yap8. In this work, we use molecular and biochemical analyses combined with computer-based structural design and molecular dynamics simulations of Yap8–DNA interactions to better understand the structural basis of DNA binding specificity determinants. We identify specific residues in the N-terminal tail preceding the basic region, which define stable association of Yap8 with its target promoter. We propose that the N-terminal tail directly interacts with DNA and stabilizes Yap8 binding to the 13 bp motif. Thus, beside the core basic region, the adjacent N-terminal region contributes to alternative DNA binding selectivity within the AP-1 family.
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Bouganim, Nathaniel, Jocelyn David, Robert Wysocki, and Dindial Ramotar. "Yap1 overproduction restores arsenite resistance to the ABC transporter deficient mutant ycf1 by activating ACR3 expression." Biochemistry and Cell Biology 79, no. 4 (2001): 441–48. http://dx.doi.org/10.1139/o01-033.
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Ycf1 and Acr3 are transporters that have been previously shown to protect Saccharomyces cerevisiae cells from the toxic effects of arsenite. Ycf1 and Acr3 are positively regulated by distinct, but related bZIP transcriptional activators, Yap1 and Yap8, respectively. In this study, we show that overexpression of Yap1 complemented the arsenite hypersensitivity of the ycf1 null mutant, but only if the ACR3 gene is functional. We further show that the expression of either an ACR3-lacZ promoter fusion reporter or the endogenous ACR3 gene was stimulated by the overproduction of Yap1 upon exposure to arsenite. These data suggest that Yap1 confers arsenite resistance to the ycf1 null mutant by activating expression of the Yap8-dependent target gene, ACR3. Our data also show Yap8-dependent ACR3-lacZ expression was greatly stimulated by arsenite in a dose-dependent manner in the parental strain. However, overproduction of Yap1 in the parental strain severely limited dose-dependent activation of the reporter by arsenite. We conclude that Yap1 may compete with Yap8 for binding to the ACR3 promoter, but is unable to act as a potent activator.Key words: arsenite, ABC transporters, AP-1 factors, overproduction, element, yeast.
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Fernandes, L., C. Rodrigues-Pousada, and K. Struhl. "Yap, a novel family of eight bZIP proteins in Saccharomyces cerevisiae with distinct biological functions." Molecular and Cellular Biology 17, no. 12 (1997): 6982–93. http://dx.doi.org/10.1128/mcb.17.12.6982.
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Saccharomyces cerevisiae contains eight members of a novel and fungus-specific family of bZIP proteins that is defined by four atypical residues on the DNA-binding surface. Two of these proteins, Yap1 and Yap2, are transcriptional activators involved in pleiotropic drug resistance. Although initially described as AP-1 factors, at least four Yap proteins bind most efficiently to TTACTAA, a sequence that differs at position +/-2 from the optimal AP-1 site (TGACTCA); further, a Yap-like derivative of the AP-1 factor Gcn4 (A239Q S242F) binds efficiently to the Yap recognition sequence. Molecular modeling suggests that the Yap-specific residues make novel contacts and cause physical constraints at the +/-2 position that may account for the distinct DNA-binding specificities of Yap and AP-1 proteins. To various extents, Yap1, Yap2, Yap3, and Yap5 activate transcription from a promoter containing a Yap recognition site. Yap-dependent transcription is abolished in strains containing high levels of protein kinase A; in contrast, Gcn4 transcriptional activity is stimulated by protein kinase A. Interestingly, Yap1 transcriptional activity is stimulated by hydrogen peroxide, whereas Yap2 activity is stimulated by aminotriazole and cadmium. In addition, unlike other yap mutations tested, yap4 (cin5) mutations affect chromosome stability, and they suppress the cold-sensitive phenotype of yap1 mutant strains. Thus, members of the Yap family carry out overlapping but distinct biological functions.
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Menezes, Regina A., Catarina Amaral, Liliana Batista-Nascimento, et al. "Contribution of Yap1 towards Saccharomyces cerevisiae adaptation to arsenic-mediated oxidative stress." Biochemical Journal 414, no. 2 (2008): 301–11. http://dx.doi.org/10.1042/bj20071537.
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In the budding yeast Saccharomyces cerevisiae, arsenic detoxification involves the activation of Yap8, a member of the Yap (yeast AP-1-like) family of transcription factors, which in turn regulates ACR2 and ACR3, genes encoding an arsenate reductase and a plasma-membrane arsenite-efflux protein respectively. In addition, Yap1 is involved in the arsenic adaptation process through regulation of the expression of the vacuolar pump encoded by YCF1 (yeast cadmium factor 1 gene) and also contributing to the regulation of ACR genes. Here we show that Yap1 is also involved in the removal of ROS (reactive oxygen species) generated by arsenic compounds. Data on lipid peroxidation and intracellular oxidation indicate that deletion of YAP1 and YAP8 triggers cellular oxidation mediated by inorganic arsenic. In spite of the increased amounts of As(III) absorbed by the yap8 mutant, the enhanced transcriptional activation of the antioxidant genes such as GSH1 (γ- glutamylcysteine synthetase gene), SOD1 (superoxide dismutase 1 gene) and TRX2 (thioredoxin 2 gene) may prevent protein oxidation. In contrast, the yap1 mutant exhibits high contents of protein carbonyl groups and the GSSG/GSH ratio is severely disturbed on exposure to arsenic compounds in these cells. These results point to an additional level of Yap1 contribution to arsenic stress responses by preventing oxidative damage in cells exposed to these compounds. Transcriptional profiling revealed that genes of the functional categories related to sulphur and methionine metabolism and to the maintenance of cell redox homoeostasis are activated to mediate adaptation of the wild-type strain to 2 mM arsenate treatment.
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Kumar, Nallani Vijay, Jianbo Yang, Jitesh K. Pillai, et al. "Arsenic Directly Binds to and Activates the Yeast AP-1-Like Transcription Factor Yap8." Molecular and Cellular Biology 36, no. 6 (2015): 913–22. http://dx.doi.org/10.1128/mcb.00842-15.
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The AP-1-like transcription factor Yap8 is critical for arsenic tolerance in the yeastSaccharomyces cerevisiae. However, the mechanism by which Yap8 senses the presence of arsenic and activates transcription of detoxification genes is unknown. Here we demonstrate that Yap8 directly binds to trivalent arsenite [As(III)]in vitroandin vivoand that approximately one As(III) molecule is bound per molecule of Yap8. As(III) is coordinated by three sulfur atoms in purified Yap8, and our genetic and biochemical data identify the cysteine residues that form the binding site as Cys132, Cys137, and Cys274. As(III) binding by Yap8 does not require an additional yeast protein, and Yap8 is regulated neither at the level of localization nor at the level of DNA binding. Instead, our data are consistent with a model in which a DNA-bound form of Yap8 acts directly as an As(III) sensor. Binding of As(III) to Yap8 triggers a conformational change that in turn brings about a transcriptional response. Thus, As(III) binding to Yap8 acts as a molecular switch that converts inactive Yap8 into an active transcriptional regulator. This is the first report to demonstrate how a eukaryotic protein couples arsenic sensing to transcriptional activation.
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Lane, M. Chelsea, Jonathan D. Lenz, and Virginia L. Miller. "Proteolytic processing of the Yersinia pestis YapG autotransporter by the omptin protease Pla and the contribution of YapG to murine plague pathogenesis." Journal of Medical Microbiology 62, no. 8 (2013): 1124–34. http://dx.doi.org/10.1099/jmm.0.056275-0.
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Autotransporter protein secretion represents one of the simplest forms of secretion across Gram-negative bacterial membranes. Once secreted, autotransporter proteins either remain tethered to the bacterial surface or are released following proteolytic cleavage. Autotransporters possess a diverse array of virulence-associated functions such as motility, cytotoxicity, adherence and autoaggregation. To better understand the role of autotransporters in disease, our research focused on the autotransporters of Yersinia pestis, the aetiological agent of plague. Y. pestis strain CO92 has nine functional conventional autotransporters, referred to as Yaps for Yersinia autotransporter proteins. Three Yaps have been directly implicated in virulence using established mouse models of plague infection (YapE, YapJ and YapK). Whilst previous studies from our laboratory have shown that most of the CO92 Yaps are cell associated, YapE and YapG are processed and released by the omptin protease Pla. In this study, we identified the Pla cleavage sites in YapG that result in many released forms of YapG in Y. pestis, but not in the evolutionarily related gastrointestinal pathogen, Yersinia pseudotuberculosis, which lacks Pla. Furthermore, we showed that YapG does not contribute to Y. pestis virulence in established mouse models of bubonic and pneumonic infection. As Y. pestis has a complex life cycle involving a wide range of mammalian hosts and a flea vector for transmission, it remains to be elucidated whether YapG has a measurable role in any other stage of plague disease.
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Nair, Manoj K. M., Leon De Masi, Min Yue, et al. "Adhesive Properties of YapV and Paralogous Autotransporter Proteins of Yersinia pestis." Infection and Immunity 83, no. 5 (2015): 1809–19. http://dx.doi.org/10.1128/iai.00094-15.
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Yersinia pestisis the causative agent of plague. This bacterium evolved from an ancestral enteroinvasiveYersinia pseudotuberculosisstrain by gene loss and acquisition of new genes, allowing it to use fleas as transmission vectors. Infection frequently leads to a rapidly lethal outcome in humans, a variety of rodents, and cats. This study focuses on theY. pestisKIMyapVgene and its product, recognized as an autotransporter protein by its typical sequence, outer membrane localization, and amino-terminal surface exposure. Comparison ofYersiniagenomes revealed that DNA encoding YapV or each of three individual paralogous proteins (YapK, YapJ, and YapX) was present as a gene or pseudogene in a strain-specific manner and only inY. pestisandY. pseudotuberculosis. YapV acted as an adhesin for alveolar epithelial cells and specific extracellular matrix (ECM) proteins, as shown with recombinantEscherichia coli,Y. pestis, or purified passenger domains. Like YapV, YapK and YapJ demonstrated adhesive properties, suggesting that their previously relatedin vivoactivity is due to their capacity to modulate binding properties ofY. pestisin its hosts, in conjunction with other adhesins. A differential host-specific type of binding to ECM proteins by YapV, YapK, and YapJ suggested that these proteins participate in broadening the host range ofY. pestis. A phylogenic tree including 36Y. pestisstrains highlighted an association between the gene profile for the four paralogous proteins and the geographic location of the corresponding isolated strains, suggesting an evolutionary adaption ofY. pestisto specific local animal hosts or reservoirs.
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Guerra-Moreno, Angel, Miguel A. Prado, Jessie Ang, et al. "Thiol-based direct threat sensing by the stress-activated protein kinase Hog1." Science Signaling 12, no. 609 (2019): eaaw4956. http://dx.doi.org/10.1126/scisignal.aaw4956.
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The yeast stress-activated protein kinase Hog1 is best known for its role in mediating the response to osmotic stress, but it is also activated by various mechanistically distinct environmental stressors, including heat shock, endoplasmic reticulum stress, and arsenic. In the osmotic stress response, the signal is sensed upstream and relayed to Hog1 through a kinase cascade. Here, we identified a mode of Hog1 function whereby Hog1 senses arsenic through a direct physical interaction that requires three conserved cysteine residues located adjacent to the catalytic loop. These residues were essential for Hog1-mediated protection against arsenic, were dispensable for the response to osmotic stress, and promoted the nuclear localization of Hog1 upon exposure of cells to arsenic. Hog1 promoted arsenic detoxification by stimulating phosphorylation of the transcription factor Yap8, promoting Yap8 nuclear localization, and stimulating the transcription of the only known Yap8 targets, ARR2 and ARR3, both of which encode proteins that promote arsenic efflux. The related human kinases ERK1 and ERK2 also bound to arsenic in vitro, suggesting that this may be a conserved feature of some members of the mitogen-activated protein kinase (MAPK) family. These data provide a mechanistic basis for understanding how stress-activated kinases can sense distinct threats and perform highly specific adaptive responses.
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Ferreira, R. T., R. A. Menezes, and C. Rodrigues-Pousada. "E4-Ubiquitin ligase Ufd2 stabilizes Yap8 and modulates arsenic stress responses independent of the U-box motif." Biology Open 4, no. 9 (2015): 1122–31. http://dx.doi.org/10.1242/bio.010405.
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Menezes, Regina Andrade, Catarina Pimentel, Ana Rita Courelas Silva, et al. "Mediator, SWI/SNF and SAGA complexes regulate Yap8-dependent transcriptional activation of ACR2 in response to arsenate." Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 1860, no. 4 (2017): 472–81. http://dx.doi.org/10.1016/j.bbagrm.2017.02.001.
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Amaral, Catarina, Catarina Pimentel, Rute G. Matos, Cecília M. Arraiano, Manolis Matzapetakis, and Claudina Rodrigues-Pousada. "Two Residues in the Basic Region of the Yeast Transcription Factor Yap8 Are Crucial for Its DNA-Binding Specificity." PLoS ONE 8, no. 12 (2013): e83328. http://dx.doi.org/10.1371/journal.pone.0083328.
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Rouleau, Cecile, Arun T. Pores Fernando, Justin H. Hwang, et al. "Transformation by Polyomavirus Middle T Antigen Involves a Unique Bimodal Interaction with the Hippo Effector YAP." Journal of Virology 90, no. 16 (2016): 7032–45. http://dx.doi.org/10.1128/jvi.00417-16.
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ABSTRACTMurine polyomavirus has repeatedly provided insights into tumorigenesis, revealing key control mechanisms such as tyrosine phosphorylation and phosphoinositide 3-kinase (PI3K) signaling. We recently demonstrated that polyomavirus small T antigen (ST) binds YAP, a major effector of Hippo signaling, to regulate differentiation. Here we characterize YAP as a target of middle T antigen (MT) important for transformation. Through a surface including residues R103 and D182, wild-type MT binds to the YAP WW domains. Mutation of either R103 or D182 of MT abrogates YAP binding without affecting binding to other signaling molecules or the strength of PI3K or Ras signaling. Either genetic abrogation of YAP binding to MT or silencing of YAP via short hairpin RNA (shRNA) reduced MT transformation, suggesting that YAP makes a positive contribution to the transformed phenotype. MT targets YAP both by activating signaling pathways that affect it and by binding to it. MT signaling, whether from wild-type MT or the YAP-binding MT mutant, promoted YAP phosphorylation at S127 and S381/397 (YAP2/YAP1). Consistent with the known functions of these phosphorylated serines, MT signaling leads to the loss of YAP from the nucleus and degradation. Binding of YAP to MT brings it together with protein phosphatase 2A (PP2A), leading to the dephosphorylation of YAP in the MT complex. It also leads to the enrichment of YAP in membranes. Taken together, these results indicate that YAP promotes MT transformation via mechanisms that may depart from YAP's canonical oncogenic transcriptional activation functions.IMPORTANCEThe highly conserved Hippo/YAP pathway is important for tissue development and homeostasis. Increasingly, changes in this pathway are being associated with cancer. Middle T antigen (MT) is the primary polyomavirus oncogene responsible for tumor formation. In this study, we show that MT signaling promotes YAP phosphorylation, loss from the nucleus, and increased turnover. Notably, MT genetics demonstrate that YAP binding to MT is important for transformation. Because MT also binds PP2A, YAP bound to MT is dephosphorylated, stabilized, and localized to membranes. Taken together, these results indicate that YAP promotes MT transformation via mechanisms that depart from YAP's canonical oncogenic transcriptional activation functions.
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Wu, A. L., and W. S. Moye-Rowley. "GSH1, which encodes gamma-glutamylcysteine synthetase, is a target gene for yAP-1 transcriptional regulation." Molecular and Cellular Biology 14, no. 9 (1994): 5832–39. http://dx.doi.org/10.1128/mcb.14.9.5832.
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Changes in gene dosage of the YAP1 gene, encoding the yAP-1 transcriptional regulatory protein, cause profound alterations in cellular drug and metal resistance. Previous studies on yAP-1 action in yeast cells have used the AP-1 response element (ARE) from simian virus 40 as an artificial site for yAP-1-mediated transcriptional activation. No authentic yeast target sites for control of gene expression by yAP-1 are known. Here we show that the GSH1 gene, encoding gamma-glutamylcysteine synthetase, is transcriptionally responsive to the yAP-1 protein. GSH1 encodes the rate-limiting step in yeast glutathione biosynthesis and contains within its promoter region a DNA element that matches the ARE in 11 of 12 positions. The GSH1 yAP-1 response element (YRE) was recognized by yAP-1 protein in vitro. Northern (RNA) blot analysis showed that GSH1 mRNA levels were responsive to YAP1 gene dosage. A site-directed mutation in the YRE that blocked yAP-1 binding in vitro prevented the mutant GSH1 promoter from responding to elevation in YAP1 gene dosage. A delta gsh1 mutant strain was constructed and unable to grow in the absence of exogenous glutathione. A mutant GSH1 gene lacking the YRE was unable to confer normal cadmium tolerance, although other yAP-1-mediated phenotypes remained normal. Thus, GSH1 is one of several genes that are transcriptionally controlled by yAP-1 and influence drug resistance.
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Wu, A. L., and W. S. Moye-Rowley. "GSH1, which encodes gamma-glutamylcysteine synthetase, is a target gene for yAP-1 transcriptional regulation." Molecular and Cellular Biology 14, no. 9 (1994): 5832–39. http://dx.doi.org/10.1128/mcb.14.9.5832-5839.1994.
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Changes in gene dosage of the YAP1 gene, encoding the yAP-1 transcriptional regulatory protein, cause profound alterations in cellular drug and metal resistance. Previous studies on yAP-1 action in yeast cells have used the AP-1 response element (ARE) from simian virus 40 as an artificial site for yAP-1-mediated transcriptional activation. No authentic yeast target sites for control of gene expression by yAP-1 are known. Here we show that the GSH1 gene, encoding gamma-glutamylcysteine synthetase, is transcriptionally responsive to the yAP-1 protein. GSH1 encodes the rate-limiting step in yeast glutathione biosynthesis and contains within its promoter region a DNA element that matches the ARE in 11 of 12 positions. The GSH1 yAP-1 response element (YRE) was recognized by yAP-1 protein in vitro. Northern (RNA) blot analysis showed that GSH1 mRNA levels were responsive to YAP1 gene dosage. A site-directed mutation in the YRE that blocked yAP-1 binding in vitro prevented the mutant GSH1 promoter from responding to elevation in YAP1 gene dosage. A delta gsh1 mutant strain was constructed and unable to grow in the absence of exogenous glutathione. A mutant GSH1 gene lacking the YRE was unable to confer normal cadmium tolerance, although other yAP-1-mediated phenotypes remained normal. Thus, GSH1 is one of several genes that are transcriptionally controlled by yAP-1 and influence drug resistance.
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Cartwright, Gemma M., and Barry Scott. "Redox Regulation of an AP-1-Like Transcription Factor, YapA, in the Fungal Symbiont Epichloë festucae." Eukaryotic Cell 12, no. 10 (2013): 1335–48. http://dx.doi.org/10.1128/ec.00129-13.
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ABSTRACTOne of the central regulators of oxidative stress inSaccharomyces cerevisiaeis Yap1, a bZIP transcription factor of the AP-1 family. In unstressed cells, Yap1 is reduced and cytoplasmic, but in response to oxidative stress, it becomes oxidized and accumulates in the nucleus. To date, there have been no reports on the role of AP-1-like transcription factors in symbiotic fungi. An ortholog of Yap1, named YapA, was identified in the genome of the grass symbiontEpichloë festucaeand shown to complement anS. cerevisiaeΔyap1mutant. Hyphae of theE. festucaeΔyapAstrain were sensitive to menadione and diamide but resistant to H2O2, KO2, andtert-butyl hydroperoxide (t-BOOH). In contrast, conidia of the ΔyapAstrain were very sensitive to H2O2and failed to germinate. Using a PcatA-eGFPdegron-tagged reporter, YapA was shown to be required for expression of a spore-specific catalase gene,catA. Although YapA-EGFP localized to the nucleus in response to host reactive oxygen species during seedling infection, there was no difference in whole-plant and cellular phenotypes of plants infected with the ΔyapAstrain compared to the wild-type strain. Homologs of theS. cerevisiaeandSchizosaccharomyces pomberedox-sensing proteins (Gpx3 and Tpx1, respectively) did not act as redox sensors for YapA inE. festucae. In response to oxidative stress, YapA-EGFP localized to the nuclei ofE. festucaeΔgpxC, ΔtpxA, and ΔgpxCΔtpxAcells to the same degree as that in wild-type cells. These results show thatE. festucaehas a robust system for countering oxidative stress in culture andin plantabut that Gpx3- or Tpx1-like thiol peroxidases are dispensable for activation of YapA.
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Gabriel, Brendan M., D. Lee Hamilton, Annie M. Tremblay, and Henning Wackerhage. "The Hippo signal transduction network for exercise physiologists." Journal of Applied Physiology 120, no. 10 (2016): 1105–17. http://dx.doi.org/10.1152/japplphysiol.01076.2015.
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The ubiquitous transcriptional coactivators Yap (gene symbol Yap1) and Taz (gene symbol Wwtr1) regulate gene expression mainly by coactivating the Tead transcription factors. Being at the center of the Hippo signaling network, Yap and Taz are regulated by the Hippo kinase cassette and additionally by a plethora of exercise-associated signals and signaling modules. These include mechanotransduction, the AKT-mTORC1 network, the SMAD transcription factors, hypoxia, glucose homeostasis, AMPK, adrenaline/epinephrine and angiotensin II through G protein-coupled receptors, and IL-6. Consequently, exercise should alter Hippo signaling in several organs to mediate at least some aspects of the organ-specific adaptations to exercise. Indeed, Tead1 overexpression in muscle fibers has been shown to promote a fast-to-slow fiber type switch, whereas Yap in muscle fibers and cardiomyocytes promotes skeletal muscle hypertrophy and cardiomyocyte adaptations, respectively. Finally, genome-wide association studies in humans have linked the Hippo pathway members LATS2, TEAD1, YAP1, VGLL2, VGLL3, and VGLL4 to body height, which is a key factor in sports.
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Cheng, Wen-Chih, Osnat Bohana-Kashtan, Sebastien Morisot, et al. "The YAP Transcriptional Co-Activator Is Not Required for Mouse Hematopoiesis, at Steady State or After 5FU Treatment." Blood 116, no. 21 (2010): 1592. http://dx.doi.org/10.1182/blood.v116.21.1592.1592.
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Abstract Abstract 1592 The Yes-associated protein (YAP) is a transcriptional co-activator that interacts with many transcription factors, including RUNX2, p73, ERBB4, PEBP2α, p53BP2, SMAD7 and the TEAD/TEF proteins. Recently, it has been established that YAP is the major downstream molecule of the evolutionarily conserved Hippo signaling pathway. First elucidated in Drosophila, the Hippo signaling pathway controls organ size by regulating apoptosis and proliferation. Beginning a kinase cascade, the MST1/MST2 kinases (fly ortholog: Hippo) cooperate with the WW domain-containing SAV1 (fly ortholog: Salvador) to phosphorylate and activate the LATS1/LATS2 kinases (fly ortholog: Warts). In turn, activated LATS1/LATS2 phosphorylate and inactivate YAP (fly ortholog: Yorkie). Inactivated YAP binds to 14-3-3 and is kept in the cytosol. In contrast, unphosphorylated YAP binds to TEAD family transcription factors (fly ortholog: Scalloped) and the complex transactivates genes including cell cycle regulators (e.g. cyclin) and cell death inhibitors (e.g. IAPs, inhibitor of apoptosis). Therefore, inactivation of MST or LATS kinase, or overexpression of YAP results in organ/tissue overgrowth characterized by excessive cell proliferation and diminished apoptosis in both fly and mammals. In two transgenic mouse models, overexpression of YAP1 in liver results in reversible increase in liver size due to increased proliferation and decreased cell death of hepatocytes. Several pieces of evidence suggest that YAP regulates stem cell self-renewal and differentiation. First, transcriptional profiling of mouse stem cells (hematopoietic, neuronal and embryonic) identified both YAP1 and TEAD2 as 2 of the only 14 transcription factors commonly expressed in all 3 types of stem cell. Second, in many adult human tissues (e.g. intestine, lung, pancreas), YAP1 is preferentially expressed in stem-progenitor cell compartments. Third, in mouse intestine and chick neural tubes, overexpression of YAP results in expansion of intestinal or neural stem-progenitor cells, as well as inhibition of progenitor cell differentiation in vivo. Finally, it has been shown that YAP expression decreases during mouse ES cell differentiation. Ectopic expression of YAP can maintain ES cell pluripotency and prevent differentiation both in vitro and in vivo. Given that YAP has a proven role in regulating stem-progenitor cells in multiple tissue and multiple organisms, we set out to investigate whether YAP also regulate hematopoetic stem-progenitors in mouse and human. In conditional YAP knockout mice with a specific deletion of YAP expression in the hematopoetic system, we found no abnormalities at steady state in hemtaopoietic lineages, as assessed by CBC (complete blood counts) or immunophenotypic analysis. In addition, the YAP-null hematopietic stem-progenitors (HSPCs) had no change in vitro hematopoietic colony-forming cells. Furthermore, 5-fluorouracil treatment did not reveal a significant difference in blood cell numbers or types, between wild type and YAP-null mice. Although these results in mice suggest that YAP appears not to be required in hematopoiesis, overexpression of YAP, which promotes stem-progenitor cell proliferation in other tissues, may still provide an excellent opportunity to drive HSPC expansion. Disclosures: No relevant conflicts of interest to declare.
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NEVITT, Tracy, Jorge PEREIRA, Dulce AZEVEDO, Paulo GUERREIRO, and Claudina RODRIGUES-POUSADA. "Expression of YAP4 in Saccharomyces cerevisiae under osmotic stress." Biochemical Journal 379, no. 2 (2004): 367–74. http://dx.doi.org/10.1042/bj20031127.
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YAP4, a member of the yeast activator protein (YAP) gene family, is induced in response to osmotic shock in the yeast Saccharomyces cerevisiae. The null mutant displays mild and moderate growth sensitivity at 0.4 M and 0.8 M NaCl respectively, a fact that led us to analyse YAP4 mRNA levels in the hog1 (high osmolarity glycerol) mutant. The data obtained show a complete abolition of YAP4 gene expression in this mutant, placing YAP4 under the HOG response pathway. YAP4 overexpression not only suppresses the osmosensitivity phenotype of the yap4 mutant but also relieves that of the hog1 mutant. Induction, under the conditions tested so far, requires the presence of the transcription factor Msn2p, but not of Msn4p, as YAP4 mRNA levels are depleted by at least 75% in the msn2 mutant. This result was further substantiated by the fact that full YAP4 induction requires the two more proximal stress response elements. Furthermore we find that GCY1, encoding a putative glycerol dehydrogenase, GPP2, encoding a NAD-dependent glycerol-3-phosphate phosphatase, and DCS2, a homologue to a decapping enzyme, have decreased mRNA levels in the yap4-deleted strain. Our data point to a possible, as yet not entirely understood, role of the YAP4 in osmotic stress response.
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Yoo, Lee, Jun, et al. "The YAP1–NMU Axis Is Associated with Pancreatic Cancer Progression and Poor Outcome: Identification of a Novel Diagnostic Biomarker and Therapeutic Target." Cancers 11, no. 10 (2019): 1477. http://dx.doi.org/10.3390/cancers11101477.
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Yes-associated protein (YAP)-1 is highly upregulated in pancreatic cancer and associated with tumor progression. However, little is known about the role of YAP1 and related genes in pancreatic cancer. Here, we identified target genes regulated by YAP1 and explored their role in pancreatic cancer progression and the related clinical implications. Analysis of different pancreatic cancer databases showed that Neuromedin U (NMU) expression was positively correlated with YAP1 expression in the tumor group. The Cancer Genome Atlas data indicated that high YAP1 and NMU expression levels were associated with poor mean and overall survival. YAP1 overexpression induced NMU expression and transcription and promoted cell motility in vitro and tumor metastasis in vivo via upregulation of epithelial–mesenchymal transition (EMT), whereas specific inhibition of NMU in cells stably expressing YAP1 had the opposite effect in vitro and in vivo. To define this functional association, we identified a transcriptional enhanced associate domain (TEAD) binding site in the NMU promoter and demonstrated that YAP1–TEAD binding upstream of the NMU gene regulated its transcription. These results indicate that the identified positive correlation between YAP1 and NMU is a potential novel drug target and biomarker in metastatic pancreatic cancer.
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Oka, Tsutomu, Eline Remue, Kris Meerschaert, et al. "Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling1." Biochemical Journal 432, no. 3 (2010): 461–78. http://dx.doi.org/10.1042/bj20100870.
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The Hippo pathway regulates the size of organs by controlling two opposing processes: proliferation and apoptosis. YAP2 (Yes kinase-associated protein 2), one of the three isoforms of YAP, is a WW domain-containing transcriptional co-activator that acts as the effector of the Hippo pathway in mammalian cells. In addition to WW domains, YAP2 has a PDZ-binding motif at its C-terminus. We reported previously that this motif was necessary for YAP2 localization in the nucleus and for promoting cell detachment and apoptosis. In the present study, we show that the tight junction protein ZO (zonula occludens)-2 uses its first PDZ domain to form a complex with YAP2. The endogenous ZO-2 and YAP2 proteins co-localize in the nucleus. We also found that ZO-2 facilitates the nuclear localization and pro-apoptotic function of YAP2, and that this activity of ZO-2 is PDZ-domain-dependent. The present paper is the first report on a PDZ-based nuclear translocation mechanism. Moreover, since the Hippo pathway acts as a tumour suppressor pathway, the YAP2–ZO-2 complex could represent a target for cancer therapy.
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Saito, Kanako, Ryotaro Kawasoe, Hiroshi Sasaki, Ayano Kawaguchi, and Takaki Miyata. "Neural Progenitor Cells Undergoing Yap/Tead-Mediated Enhanced Self-Renewal Form Heterotopias More Easily in the Diencephalon than in the Telencephalon." Neurochemical Research 43, no. 1 (2018): 180–89. http://dx.doi.org/10.1007/s11064-017-2390-x.
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Abstract Spatiotemporally ordered production of cells is essential for brain development. Normally, most undifferentiated neural progenitor cells (NPCs) face the apical (ventricular) surface of embryonic brain walls. Pathological detachment of NPCs from the apical surface and their invasion of outer neuronal territories, i.e., formation of NPC heterotopias, can disrupt the overall structure of the brain. Although NPC heterotopias have previously been observed in a variety of experimental contexts, the underlying mechanisms remain largely unknown. Yes-associated protein 1 (Yap1) and the TEA domain (Tead) proteins, which act downstream of Hippo signaling, enhance the stem-like characteristics of NPCs. Elevated expression of Yap1 or Tead in the neural tube (future spinal cord) induces massive NPC heterotopias, but Yap/Tead-induced expansion of NPCs in the developing brain has not been previously reported to produce NPC heterotopias. To determine whether NPC heterotopias occur in a regionally characteristic manner, we introduced the Yap1-S112A or Tead-VP16 into NPCs of the telencephalon and diencephalon, two neighboring but distinct forebrain regions, of embryonic day 10 mice by in utero electroporation, and compared NPC heterotopia formation. Although NPCs in both regions exhibited enhanced stem-like behaviors, heterotopias were larger and more frequent in the diencephalon than in the telencephalon. This result, the first example of Yap/Tead-induced NPC heterotopia in the forebrain, reveals that Yap/Tead-induced NPC heterotopia is not specific to the neural tube, and also suggests that this phenomenon depends on regional factors such as the three-dimensional geometry and assembly of these cells.
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Szulzewsky, Frank, Pia Hoellerbauer, Hua-Jun Wu, et al. "GENE-04. THE ONCOGENIC FUNCTIONS OF YAP1-GENE FUSIONS CAN BE INHIBITED BY DISRUPTION OF YAP1-TEAD INTERACTION." Neuro-Oncology 21, Supplement_6 (2019): vi98. http://dx.doi.org/10.1093/neuonc/noz175.406.
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Abstract Supratentorial ependymoma can be sub-stratified into clinically relevant subtypes characterized by distinct molecular features. The subtype defined by high YAP1 activity harbored two distinct YAP1 gene fusions, YAP1-MAMLD1 and YAP1-FAM118B. In addition, YAP1 gene fusions have been detected in several other cancer types, including Epithelioid Hemangioendothelioma and Endocervical Adenocarcinoma. YAP1 is a key transcriptional co-activator and proto-oncogene that is negatively regulated by the Hippo pathway. Here, we show that both YAP1-MAMLD1 and YAP1-FAM118B, as well as additional YAP1 fusion genes found in other cancer types, are potent oncogenic drivers that cause tumor formation in the brain and the hindlimb in mice upon overexpression by somatic cell gene transfer. Using different in vitro assays, including Luciferase, RNA-, and ChIP Seq, we show that both the N-terminal YAP1 part and the C-terminal fusion partners exert activity. We can show that the YAP1 activity still relies on the binding to TEAD transcription factors, whereas the C terminal activity does not. Furthermore, the different fusion proteins have become independent from negative Hippo pathway signaling by constitutive nuclear localization and protection from degradation. In addition, by introducing point mutations and truncations to block the YAP1 and the MAMLD1 function we can show that the activity of both halves contributes to the oncogenic function of YAP1-MAMLD1. Using in vitro and in vivo assays we can show that pharmacological and genetic ablation of YAP-TEAD interaction diminishes the oncogenic potential of the fusions, indicating that this might be a potential therapeutic approach for these tumors in the future.
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Bossier, P., L. Fernandes, D. Rocha, and C. Rodrigues-Pousada. "Overexpression of YAP2, coding for a new yAP protein, and YAP1 in Saccharomyces cerevisiae alleviates growth inhibition caused by 1,10-phenanthroline." Journal of Biological Chemistry 268, no. 31 (1993): 23640–45. http://dx.doi.org/10.1016/s0021-9258(19)49510-0.
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Li, Liangtao, Dustin Bagley, Diane M. Ward, and Jerry Kaplan. "Yap5 Is an Iron-Responsive Transcriptional Activator That Regulates Vacuolar Iron Storage in Yeast." Molecular and Cellular Biology 28, no. 4 (2007): 1326–37. http://dx.doi.org/10.1128/mcb.01219-07.
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ABSTRACT The transporter Ccc1 imports iron into the vacuole, which is the major site of iron storage in fungi and plants. CCC1 mRNA is destabilized under low-iron conditions by the binding of Cth1 and Cth2 to the 3′ untranslated region (S. Puig, E. Askeland, and D. J. Thiele, Cell 120:99-110, 2005). Here, we show that the transcription of CCC1 is stimulated by iron through a Yap consensus site in the CCC1 promoter. We identified YAP5 as being the iron-sensitive transcription factor and show that a yap5Δ strain is sensitive to high iron. Green fluorescent protein-tagged Yap5 is localized to the nucleus and occupies the CCC1 promoter independent of the iron concentration. Yap5 contains two cysteine-rich domains, and the mutation of the cysteines to alanines in each of the domains affects the transcription of CCC1 but not DNA binding. The fusion of the Yap5 cysteine-containing domains to a GAL4 DNA binding domain results in iron-sensitive GAL1-lacZ expression. Iron affects the sulfhydryl status of Yap5, which is indicative of the generation of intramolecular disulfide bonds. These results show that Yap5 is an iron-sensing transcription factor and that iron regulates transcriptional activation.
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Xia, Wenlong, Libo Su, and Jianwei Jiao. "Cold-induced protein RBM3 orchestrates neurogenesis via modulating Yap mRNA stability in cold stress." Journal of Cell Biology 217, no. 10 (2018): 3464–79. http://dx.doi.org/10.1083/jcb.201801143.
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In mammals, a constant body temperature is an important basis for maintaining life activities. Here, we show that when pregnant mice are subjected to cold stress, the expression of RBM3, a cold-induced protein, is increased in the embryonic brain. When RBM3 is knocked down or knocked out in cold stress, embryonic brain development is more seriously affected, exhibiting abnormal neuronal differentiation. By detecting the change in mRNA expression during maternal cold stress, we demonstrate that Yap and its downstream molecules are altered at the RNA level. By analyzing RNA-binding motif of RBM3, we find that there are seven binding sites in 3′UTR region of Yap1 mRNA. Mechanistically, RBM3 binds to Yap1-3′UTR, regulates its stability, and affects the expression of YAP1. RBM3 and YAP1 overexpression can partially rescue the brain development defect caused by RBM3 knockout in cold stress. Collectively, our data demonstrate that cold temperature affects brain development, and RBM3 acts as a key protective regulator in cold stress.
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Archibald, Andrew, Maia Al-Masri, Alyson Liew-Spilger, and Luke McCaffrey. "Atypical protein kinase C induces cell transformation by disrupting Hippo/Yap signaling." Molecular Biology of the Cell 26, no. 20 (2015): 3578–95. http://dx.doi.org/10.1091/mbc.e15-05-0265.
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Epithelial cells are major sites of malignant transformation. Atypical protein kinase C (aPKC) isoforms are overexpressed and activated in many cancer types. Using normal, highly polarized epithelial cells (MDCK and NMuMG), we report that aPKC gain of function overcomes contact inhibited growth and is sufficient for a transformed epithelial phenotype. In 2D cultures, aPKC induced cells to grow as stratified epithelia, whereas cells grew as solid spheres of nonpolarized cells in 3D culture. aPKC associated with Mst1/2, which uncoupled Mst1/2 from Lats1/2 and promoted nuclear accumulation of Yap1. Of importance, Yap1 was necessary for aPKC-mediated overgrowth but did not restore cell polarity defects, indicating that the two are separable events. In MDCK cells, Yap1 was sequestered to cell–cell junctions by Amot, and aPKC overexpression resulted in loss of Amot expression and a spindle-like cell phenotype. Reexpression of Amot was sufficient to restore an epithelial cobblestone appearance, Yap1 localization, and growth control. In contrast, the effect of aPKC on Hippo/Yap signaling and overgrowth in NMuMG cells was independent of Amot. Finally, increased expression of aPKC in human cancers strongly correlated with increased nuclear accumulation of Yap1, indicating that the effect of aPKC on transformed growth by deregulating Hippo/Yap1 signaling may be clinically relevant.
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Huang, Long Shuang, Tara Sudhadevi, Panfeng Fu, et al. "Sphingosine Kinase 1/S1P Signaling Contributes to Pulmonary Fibrosis by Activating Hippo/YAP Pathway and Mitochondrial Reactive Oxygen Species in Lung Fibroblasts." International Journal of Molecular Sciences 21, no. 6 (2020): 2064. http://dx.doi.org/10.3390/ijms21062064.
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The sphingosine kinase 1 (SPHK1)/sphingosine–1–phosphate (S1P) signaling axis is emerging as a key player in the development of idiopathic pulmonary fibrosis (IPF) and bleomycin (BLM)-induced lung fibrosis in mice. Recent evidence implicates the involvement of the Hippo/Yes-associated protein (YAP) 1 pathway in lung diseases, including IPF, but its plausible link to the SPHK1/S1P signaling pathway is unclear. Herein, we demonstrate the increased co-localization of YAP1 with the fibroblast marker FSP1 in the lung fibroblasts of BLM-challenged mice, and the genetic deletion of Sphk1 in mouse lung fibroblasts (MLFs) reduced YAP1 localization in fibrotic foci. The PF543 inhibition of SPHK1 activity in mice attenuated YAP1 co-localization with FSP1 in lung fibroblasts. In vitro, TGF-β stimulated YAP1 translocation to the nucleus in primary MLFs, and the deletion of Sphk1 or inhibition with PF543 attenuated TGF-β-mediated YAP1 nuclear localization. Moreover, the PF543 inhibition of SPHK1, or the verteporfin inhibition of YAP1, decreased the TGF-β- or BLM-induced mitochondrial reactive oxygen species (mtROS) in human lung fibroblasts (HLFs) and the expression of fibronectin (FN) and alpha-smooth muscle actin (α-SMA). Furthermore, scavenging mtROS with MitoTEMPO attenuated the TGF-β-induced expression of FN and α-SMA. The addition of the S1P antibody to HLFs reduced TGF-β- or S1P-mediated YAP1 activation, mtROS, and the expression of FN and α-SMA. These results suggest a role for SPHK1/S1P signaling in TGF-β-induced YAP1 activation and mtROS generation, resulting in fibroblast activation, a critical driver of pulmonary fibrosis.
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Fu, David, Xiangmin Lv, Guohua Hua, et al. "YAP regulates cell proliferation, migration, and steroidogenesis in adult granulosa cell tumors." Endocrine-Related Cancer 21, no. 2 (2014): 297–310. http://dx.doi.org/10.1530/erc-13-0339.
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The Hippo signaling pathway has been implicated as a conserved regulator of organ size in both Drosophila and mammals. Yes-associated protein (YAP), the central component of the Hippo signaling cascade, functions as an oncogene in several malignancies. Ovarian granulosa cell tumors (GCT) are characterized by enlargement of the ovary, excess production of estrogen, a high frequency of recurrence, and the potential for malignancy and metastasis. Whether the Hippo pathway plays a role in the pathogenesis of GCT is unknown. This study was conducted to examine the expression of YAP in human adult GCTs and to determine the role of YAP in the proliferation and steroidogenesis of GCT cells. Compared with age-matched normal human ovaries, GCT tissues exhibited higher levels of YAP expression. YAP protein was predominantly expressed in the nucleus of tumor cells, whereas the non-tumor ovarian stromal cells expressed very low levels of YAP. YAP was also expressed in cultured primary human granulosa cells and in KGN and COV434 GCT cell lines. siRNA-mediated knockdown of YAP in KGN cells resulted in a significant reduction in cell proliferation (P<0.001). Conversely, overexpression of wild type YAP or a constitutively active YAP (YAP1) mutant resulted in a significant increase in KGN cell proliferation and migration. Moreover, YAP knockdown reduced FSH-induced aromatase (CYP19A1) protein expression and estrogen production in KGN cells. These results demonstrate that YAP plays an important role in the regulation of GCT cell proliferation, migration, and steroidogenesis. Targeting the Hippo/YAP pathway may provide a novel therapeutic approach for GCT.
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Rietzschel, Nicole, Antonio J. Pierik, Eckhard Bill, Roland Lill, and Ulrich Mühlenhoff. "The Basic Leucine Zipper Stress Response Regulator Yap5 Senses High-Iron Conditions by Coordination of [2Fe-2S] Clusters." Molecular and Cellular Biology 35, no. 2 (2014): 370–78. http://dx.doi.org/10.1128/mcb.01033-14.
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Iron is an essential, yet at elevated concentrations toxic trace element. To date, the mechanisms of iron sensing by eukaryotic iron-responsive transcription factors are poorly understood. TheSaccharomyces cerevisiaetranscription factor Yap5, a member of the Yap family of bZIP stress response regulators, administrates the adaptive response to high-iron conditions. Despite the central role of the iron-sensing process for cell viability, the molecule perceived by Yap5 and the underlying regulatory mechanisms are unknown. Here, we show that Yap5 senses high-iron conditions by two Fe/S clusters bound to its activator domain (Yap5-AD). The more stable iron-regulatory Fe/S cluster at the N-terminal cysteine-rich domain (n-CRD) of Yap5 is detectedin vivoandin vitro. The second cluster coordinated by the C-terminal CRD can only be shown after chemical reconstitution, since it is bound in a labile fashion. Both clusters are of the [2Fe-2S] type as characterized by UV/visible (UV/Vis), circular dichroism, electron paramagnetic resonance (EPR), and Mössbauer spectroscopy. Fe/S cluster binding to Yap5-AD induces a conformational change that may activate transcription. The cluster-binding motif of the n-CRD domain is highly conserved in HapX-like transcription factors of pathogenic fungi and thus may represent a general sensor module common to many eukaryotic stress response regulators.
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Khalil, Md Imtiaz, Ishita Ghosh, Vibha Singh, Jing Chen, Haining Zhu, and Arrigo De Benedetti. "NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output." Cancers 12, no. 12 (2020): 3666. http://dx.doi.org/10.3390/cancers12123666.
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Most prostate cancer (PCa) deaths result from progressive failure in standard androgen deprivation therapy (ADT), leading to metastatic castration-resistant PCa (mCRPC); however, the mechanism and key players leading to this are not fully understood. While studying the role of tousled-like kinase 1 (TLK1) and never in mitosis gene A (NIMA)-related kinase 1 (NEK1) in a DNA damage response (DDR)-mediated cell cycle arrest in LNCaP cells treated with bicalutamide, we uncovered that overexpression of wt-NEK1 resulted in a rapid conversion to androgen-independent (AI) growth, analogous to what has been observed when YAP1 is overexpressed. We now report that overexpression of wt-NEK1 results in accumulation of YAP1, suggesting the existence of a TLK1>NEK1>YAP1 axis that leads to adaptation to AI growth. Further, YAP1 is co-immunoprecipitated with NEK1. Importantly, NEK1 was able to phosphorylate YAP1 on six residues in vitro, which we believe are important for stabilization of the protein, possibly by increasing its interaction with transcriptional partners. In fact, knockout (KO) of NEK1 in NT1 PCa cells resulted in a parallel decrease of YAP1 level and reduced expression of typical YAP-regulated target genes. In terms of cancer potential implications, the expression of NEK1 and YAP1 proteins was found to be increased and correlated in several cancers. These include PCa stages according to Gleason score, head and neck squamous cell carcinoma, and glioblastoma, suggesting that this co-regulation is imparted by increased YAP1 stability when NEK1 is overexpressed or activated by TLK1, and not through transcriptional co-expression. We propose that the TLK1>NEK1>YAP1 axis is a key determinant for cancer progression, particularly during the process of androgen-sensitive to -independent conversion during progression to mCRPC.
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Uttagomol, Jutamas, Usama Sharif Ahmad, Ambreen Rehman, et al. "Evidence for the Desmosomal Cadherin Desmoglein-3 in Regulating YAP and Phospho-YAP in Keratinocyte Responses to Mechanical Forces." International Journal of Molecular Sciences 20, no. 24 (2019): 6221. http://dx.doi.org/10.3390/ijms20246221.
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Desmoglein 3 (Dsg3) plays a crucial role in cell-cell adhesion and tissue integrity. Increasing evidence suggests that Dsg3 acts as a regulator of cellular mechanotransduction, but little is known about its direct role in mechanical force transmission. The present study investigated the impact of cyclic strain and substrate stiffness on Dsg3 expression and its role in mechanotransduction in keratinocytes. A direct comparison was made with E-cadherin, a well-characterized mechanosensor. Exposure of oral and skin keratinocytes to equiaxial cyclic strain promoted changes in the expression and localization of junction assembly proteins. The knockdown of Dsg3 by siRNA blocked strain-induced junctional remodeling of E-cadherin and Myosin IIa. Importantly, the study demonstrated that Dsg3 regulates the expression and localization of yes-associated protein (YAP), a mechanosensory, and an effector of the Hippo pathway. Furthermore, we showed that Dsg3 formed a complex with phospho-YAP and sequestered it to the plasma membrane, while Dsg3 depletion had an impact on both YAP and phospho-YAP in their response to mechanical forces, increasing the sensitivity of keratinocytes to the strain or substrate rigidity-induced nuclear relocation of YAP and phospho-YAP. Plakophilin 1 (PKP1) seemed to be crucial in recruiting the complex containing Dsg3/phospho-YAP to the cell surface since its silencing affected Dsg3 junctional assembly with concomitant loss of phospho-YAP at the cell periphery. Finally, we demonstrated that this Dsg3/YAP pathway has an influence on the expression of YAP1 target genes and cell proliferation. Together, these findings provide evidence of a novel role for Dsg3 in keratinocyte mechanotransduction.
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Kim, Su-Lim, Hack Sun Choi, Ji-Hyang Kim, and Dong-Sun Lee. "The Antiasthma Medication Ciclesonide Suppresses Breast Cancer Stem Cells through Inhibition of the Glucocorticoid Receptor Signaling-Dependent YAP Pathway." Molecules 25, no. 24 (2020): 6028. http://dx.doi.org/10.3390/molecules25246028.
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Ciclesonide is an FDA-approved glucocorticoid used to treat asthma and allergic rhinitis. However, whether it has anticancer and anti-cancer stem cell (CSC) effects is unknown. This study focused on investigating the effect of ciclesonide on breast cancer and CSCs and determining its underlying mechanism. Here, we showed that ciclesonide inhibits breast cancer and CSC formation. Similar glucocorticoids—dexamethasone and prednisone—did not inhibit CSC formation. Ciclesonide-induced glucocorticoid receptor (GR) degradation was dependent on ubiquitination. We showed via GR small interfering RNA (siRNA) that GR plays an important role in CSC formation. We showed via western blot and immunofluorescence assays that ciclesonide reduces the nuclear level of GR. The GR antagonist RU-486 also inhibited CSC formation. Ciclesonide reduced the protein level of the Hippo transducer Yes-associated protein (YAP). GR siRNA induced a decrease in YAP protein expression and inhibited mammosphere formation. The YAP inhibitor verteporfin inhibited CSC formation and transcription of the connective tissue growth factor and cysteine-rich protein 61 genes. The GR/YAP1 pathway regulated breast CSC formation. We showed that the GR/YAP signaling pathway regulates breast CSC formation and revealed a new approach for targeting GR and YAP to inhibit CSC formation.
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Xiang, Cheng, Jia Li, Liaoliao Hu, et al. "Hippo Signaling Pathway Reveals a Spatio-Temporal Correlation with the Size of Primordial Follicle Pool in Mice." Cellular Physiology and Biochemistry 35, no. 3 (2015): 957–68. http://dx.doi.org/10.1159/000369752.
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Background: The Hippo signaling pathway, a highly conserved cell signaling system, exists in most multicellular organisms and regulates cell proliferation, differentiation, and apoptosis. It has been reported that the members of Hippo signaling are expressed in mammalian ovaries, but the exact functions of this pathway in primordial follicle development remains unclear. Methods: To analyze the spatio-temporal correlation between the core component of Hippo pathway and the size of primordial follicle pool, Western blot, Real-time PCR and immunohistochemistry were used, and the expression and localization of MST1, LATS2 and YAP1 mRNA and protein were examined in 3 d, 1 m, 5 m, 16 m postnatal mice ovary and the culture model of mice primordial follicle in vitro. Results: Both the protein and mRNA expression of the MST1 and LATS2 were decreased significantly as mouse age increased (p < 0.05), however, the mRNA expression of them increased significantly in 16 m compared with 5 m as well as the protein expression of LATS2.The expression of YAP showed the opposite trend, and the significant protein expression of pYAP was increased before 1 m, after which no significant change was observed. Moreover, the ratio of pYAP/YAP decreased significantly. Culturing ovaries for 8 d in vitro resulted in the activation of primordial follicles in 3 d postnatal mice ovaries, and these developed into primary follicles with the expression of PCNA increasing significantly (p < 0.05). The mRNA and protein expression of MST and LATS decreased significantly (p < 0.05), and the expression of YAP increased significantly (p < 0.05, p < 0.01), whereas the ratio of pYAP/YAP decreased significantly (p < 0.05). Conclusion: The above results reveal that the expression of the core components of Hippo pathway changed during mouse follicular development, especially before and after primordial follicle activation in vitro. The primordial follicle activation may be related to the significant decrease of the ratio of pYAP1/YAP1. In conclusion, Hippo signaling pathway expressed in mice ovaries and have spatio-temporal correlation with the size of primordial follicle pool.
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Yang, Kui, Yang Zhao, Yonghao Du, and Ruixiang Tang. "Evaluation of Hippo Pathway and CD133 in Radiation Resistance in Small-Cell Lung Cancer." Journal of Oncology 2021 (January 13, 2021): 1–8. http://dx.doi.org/10.1155/2021/8842554.
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Although the Hippo pathway and CD133 have been reported to play pertinent roles in a variety of cancer, knowledge about their contribution to radiation resistance in small-cell lung cancer (SCLC) is limited. In this first-of-a-kind study, we have reported the expression of key Hippo pathway proteins in SCLC patients by immunohistochemical staining. We assessed the involvement of yes-associated protein 1 (YAP1) in radiation resistance by Cell Counting Kit-8 (CCK-8) and flow cytometry. In addition, we analysed the impact of CD133 on radiotherapy for SCLC. The mammalian Ste20-like serine/threonine kinase 2(MST2), pMST2, and pYAP1 in the Hippo pathway were not significantly associated with the disease stage and survival time in patients with SCLC. However, the pYAP1 expression showed some significance in the “YAP/TAZ subgroup” of SCLC patients. The proportion of CD133 in the SCLC cells was controlled by the YAP1 expression. The CD133 and YAP1 levels were significantly correlation with each other in tissues of SCLC patients. We sorted and isolated the CD133+ and CD133−cells in H69 and found that the cell surface glycoprotein may be associated with the radiation resistance of SCLC.In summary, we have firstly reported the expression of key Hippo pathway proteins in SCLC patients. Furthermore, we also identified that CD133 may be controlled by the expression of YAP1 in the Hippo pathway and that CD133 may be associated with the radiation resistance of SCLC.
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Mohagheghi, Sina, Zohreh Khajehahmadi та Heidar Tavilani. "Signaling in Simple Steatosis and Non-alcoholic Steatohepatitis Cirrhosis: TGF-β1, YAP/TAZ, and Hedgehog Pathway Activity". Avicenna Journal of Medical Biochemistry 6, № 2 (2018): 26–30. http://dx.doi.org/10.15171/ajmb.2018.07.
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Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of fat in the liver tissue that is usually associated with metabolic disorders. Traditionally, the disease is regarded as a spectrum of pathological conditions ranging from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH) and hepatic fibrosis with progression to cirrhosis. However, so far, there is no available explanation for the disease progression. Several signaling pathways such as transforming growth factor (TGF)-β, hedgehog (HH), and yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling are attributed to the NAFLD pathogenesis. TGF-β1 pathway component expression aligns with HH pathway ligands expression elevate in NASH cirrhosis while they decrease in SS. YAP and TAZ are two transcriptional co-activators from the Hippo signaling pathway. Similarly, the TAZ level (but not YAP1) is higher in NASH cirrhosis compared to SS. In addition, these three signaling pathways have little molecular similarity but their changes are totally similar in SS and NASH cirrhosis. The present review discusses the main changes in the expression of TGF-β, HH, and YAP/TAZ pathway components in SS and NASH cirrhosis. It is hoped that these data provide a better understanding of the mechanisms that underlie the pathophysiology of NAFLD.
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Evans, Marguerite V., Hal E. Turton, Chris M. Grant, and Ian W. Dawes. "Toxicity of Linoleic Acid Hydroperoxide toSaccharomyces cerevisiae: Involvement of a Respiration-Related Process for Maximal Sensitivity and Adaptive Response." Journal of Bacteriology 180, no. 3 (1998): 483–90. http://dx.doi.org/10.1128/jb.180.3.483-490.1998.
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ABSTRACT Linoleic acid hydroperoxide (LoaOOH) formed during free radical attack on long-chain unsaturated fatty acids is an important source of biomembrane damage and is implicated in the onset of atherosclerosis, hepatic diseases, and food rancidity. LoaOOH is toxic to wild-typeSaccharomyces cerevisiae at a very low concentration (0.2 mM) relative to other peroxides. By using isogenic mutant strains, the possible roles of glutathione (gsh1 and gsh2), glutathione reductase (glr1), respiratory competence ([rho 0] petite), and yAP-1p-mediated expression (yap1) in conferring LoaOOH resistance have been examined. Respiration-related processes were essential for maximal toxicity and adaptation, as evidenced by the fact that the [rho 0] petite mutant was most resistant to LoaOOH but could not adapt. Furthermore, when respiration was blocked by using inhibitors of respiration and mutants defective in respiratory-chain components, cells became more resistant. An important role for reduced glutathione and yAP-1 in the cellular response to LoaOOH was shown, since the yap1 and glr1mutants were more sensitive than the wild type. In addition, total glutathione peroxidase activity increased following treatment with LoaOOH, indicating a possible detoxification role for this enzyme. Yeast also showed an adaptive response when pretreated with a nonlethal dose of LoaOOH (0.05 mM) and subsequently treated with a lethal dose (0.2 mM), and de novo protein synthesis was required, since adaptation was abolished upon treatment of cells with cycloheximide (25 μg ml−1). The wild-type adaptive response to LoaOOH was independent of those for the superoxide-generating agents paraquat and menadione and also of those for the organic hydroperoxides cumene hydroperoxide and tert-butyl hydroperoxide. Pretreatment with LoaOOH induced resistance to hydrogen peroxide, while pretreatment of cells with malondialdehyde (a lipid peroxidation product) and heat shock (37°C) gave cross-adaptation to LoaOOH, indicating that yeast has effective overlapping defense systems that can detoxify fatty acid hydroperoxides directly or indirectly.
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Sharma, Jyoti, and Pavneesh Madan. "Characterisation of the Hippo signalling pathway during bovine preimplantation embryo development." Reproduction, Fertility and Development 32, no. 4 (2020): 392. http://dx.doi.org/10.1071/rd18320.
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Blastocyst formation is an important milestone during preimplantation embryo development. During murine preimplantation embryogenesis, the Hippo signalling pathway is known to play a significant role in lineage segregation and henceforth the formation of blastocysts. However, the role of this cell signalling pathway during bovine embryogenesis remains unknown. Thus, the aim of the present study was to characterise the Hippo signalling pathway during bovine preimplantation embryo development. mRNA transcripts of Hippo signalling pathway constituents (i.e. crumbs cell polarity complex component 3 (CRB3), mammalian sterile 20-like 1 (MST1), mammalian sterile 20-like 2 (MST2), Yes associated protein 1 (YAP1), transcriptional coactivator with PDZ-binding motif (TAZ)) were observed during all stages of bovine preimplantation embryo development. To evaluate the localisation of Hippo pathway components, bovine embryos at timed stages of development were stained using specific antibodies and observed under a laser confocal microscope. Although MST1/2 proteins were in the cytoplasm during various stages of bovine embryonic development, TAZ and phosphorylated (p-) YAP were detected in the nucleus during the blastocyst stages. Localisation of TAZ and p-YAP proteins was distinct in the bovine compared with mouse model, suggesting that the Hippo signalling pathway is regulated differently in early bovine embryos.
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Owonikoko, Taofeek Kunle, Bhakti Dwivedi, Zhengjia Chen, et al. "YAP1 positive small-cell lung cancer subtype is associated with the T-cell inflamed gene expression profile and confers good prognosis and long term survival." Journal of Clinical Oncology 38, no. 15_suppl (2020): 9019. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.9019.
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9019 Background: The dominant expression of transcription factors ASCL1, NeuroD1, YAP1 or POU2F3 characteristically defines four small cell lung cancer (SCLC) subtypes (SCLC-A, SCLC-N, SCLC-Y and SCLC-P). The clinical validation and biological relevance of these emerging SCLC subtypes is currently lacking. Methods: Using the Illumina TruSeq RNA Exome Kit, we generated RNA-Seq data from 61 cases of SCLC and pulmonary carcinoid to interrogate gene expression differences in SCLC subtypes as well as in survival outliers (top and bottom decile) matched for clinically relevant prognostic factors and treatment. We also assessed YAP1 protein expression in a blinded fashion by immunohistochemistry in 130 SCLC cases. Results: We successfully classified 68% of SCLC into one of the four SCLC subtypes whereas 81.5% of carcinoids did not fit into any of these categories. GSEA for differentially expressed genes between outlier subgroups showed significant upregulation of interferon gamma and interferon alpha response genes in late survivors. Moreover, a previously validated 18-gene T-cell inflamed gene expression profile was upregulated in late survivors and in the SCLC-Y subtype. Furthermore, the SCLC-Y subtype and late survivors showed higher expression of HLA gene family and reduced expression of cancer testis antigens. The median (95%CI) OS was 14 (4.3, 28.8), 16.7 (0.9, NA), 8.1 (2, 9.7) and 20.1 (0.6, 39.5) months respectively, for SCLC-A, N, P and Y subtypes. YAP-1 protein expression was positive in 17 of 130 (13%) SCLC cases. The majority of cases with positive YAP1 expression by immunohistochemistry, 12 of 17 cases (70.6%), were limited stage SCLC at the time of original diagnosis. Conclusions: SCLC subtypes have clinical implication as predictive and prognostic biomarker. SCLC-Y subtype is enriched for T-cell inflamed phenotype and long term survival, and may predict for clinical benefit of immunotherapy.
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You, Wenli, Zitong Xu, Aiting Di, et al. "Mechanism by Which Tong Xie Yao Fang Heals the Intestinal Mucosa of Rats with Ulcerative Colitis through the Hippo Pathway." Evidence-Based Complementary and Alternative Medicine 2021 (August 30, 2021): 1–11. http://dx.doi.org/10.1155/2021/5533914.
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Objective. Tong Xie Yao Fang (TXYF) is a classic and effective prescription in traditional Chinese medicine which is used to treat ulcerative colitis (UC). Our study investigated the effect of TXYF on Hippo pathway activation in UC-induced intestinal mucosa injury and explored the possible mechanism. Method. After ulcerative colitis was successfully induced by trinitrobenzene sulfonic acid (TNBS), 48 Sprague Dawley (SD) rats were randomly divided into a control group, model group, TXYF group, and sulfasalazine group and treated with the corresponding drugs for 28 days. The parameters including body weight, colon length, spleen index, and disease activity index (DAI) and histopathological characteristics were assessed. The myeloperoxidase (MPO) activity and IL-6 level in the colon mucosa were determined with the corresponding commercial kits. The expressions of the Hippo pathway components YAP1, TAZ, P-YAP, and LATS1 were detected in the colon mucosa of each group on different stages by quantitative real-time PCR (qRT-PCR) and western blotting. Immunohistochemical staining was used to evaluate the growth and apoptosis of the colon epithelium. Result. TXYF significantly improved the weight loss, colonic shortening, DAI, spleen enlargement, and histopathological score of the rats with TNBS-induced UC. TXYF also reduced the MPO activity and expression of IL-6 in the colon mucosa. Furthermore, treatment with TXYF significantly increased YAP1 expression in the early stage (3–7 days) and significantly decreased YAP1 expression in the late stage (14–28 days). In the early stage, TXYF inhibited Hippo pathway activity, which promoted proliferation and regeneration of the intestinal mucosa. In the late stage, the Hippo pathway was activated, thereby inhibiting apoptosis and promoting intestinal mucosal differentiation. Conclusion. TXYF alleviated the inflammatory response and promoted mucosal healing in rats with UC, which was probably achieved through the Hippo pathway. These results indicated that TXYF was a potential therapy for treating UC.
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Huang, L., and V. Natarajan. "ID: 116: ADNIBISTRATION OF SPHINGOSINE KINASE 1 INHIBITOR POST-BLEOMYCIN CHALLENGE ATTENUATES BLEOMYCIN-INDUCED PULMONARY FIBROSIS IN MICE: ROLE OF YAP1." Journal of Investigative Medicine 64, no. 4 (2016): 966.2–966. http://dx.doi.org/10.1136/jim-2016-000120.114.
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RationaleWe have earlier reported that sphingosine kinase 1 (SphK1) is up-regulated in lung tissues from idiopathic pulmonary fibrosis (IPF) patients and SphK1/sphingosine-1-phosphate (S1P) signaling axis plays a key role in bleomycin- and radiation-induced pulmonary fibrosis in mice. Further, SphK1 mRNA levels in PBMCs from IPF patients directly and significantly correlated with pulmonary function outcomes and overall survival. In this study, we investigated the effect of administration of PF-543, a specific SphK1 inhibitor, 7 days post-bleomycin (BLM) challenge on the development of pulmonary fibrosis in mice.ObjectivesTo determine the efficacy of PF-543 in attenuating pulmonary fibrosis in mice post BLM challenge.MethodsSphK1 inhibitor PF-543 (5 mg/kg body weight, i.p.; twice a week) was administered to control and BLM (1.5 U/kg, intratracheal) challenged mice on day 7 post BLM challenge, and development of pulmonary fibrosis was determined on day 21 by Mason-Trichrome staining of lung tissues, total collagen, fibronectin and α-SMA protein levels in lung tissues. In vitro, the effect of PF-543 on TGF-β (5 ng/ml) induced Yap1 activation, and differentiation, contraction, and proliferation of human lung fibroblast were assessed.ResultsAdministration of PF-543 to BLM treated mice on day 7 post challenge, dramatically inhibited BLM-induced lung injury, and attenuated collagen deposition and expression of fibronectin, α-SMA and TGF-β in lung tissues on day 21 post-BLM challenge. In vitro, PF-543 inhibited TGF-β induced differentiation, contraction and proliferation of human lung fibroblasts, as well as blocked TGF-β induced expression and nuclear translocation of YAP, a transcriptional co-factor involved in pulmonary fibrosis. Additionally, siRNA knockdown of YAP1 inhibited TGF-β induced fibroblast differentiation.ConclusionThese studies demonstrate ability of SphK1 inhibitor, PF-543 to ameliorate BLM-induced pulmonary fibrosis in mice when administered on day 7 after BLM challenge. Also, PF-543 blocked YAP1 activation, a co-transcriptional factor involved in pulmonary fibrosis development. Thus, PF-543 may serve as a potential therapeutic drug in treating pulmonary fibrosis. This work was supported by P01 HL098050 (VN).
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Lesuisse, E., and P. Labbe. "Effects of cadmium and of YAP1 and CAD1/YAP2 genes on iron metabolism in the yeast Saccharomyces cerevisiae." Microbiology 141, no. 11 (1995): 2937–43. http://dx.doi.org/10.1099/13500872-141-11-2937.
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Wise, Michael J. "YAP3." ACM SIGCSE Bulletin 28, no. 1 (1996): 130–34. http://dx.doi.org/10.1145/236462.236525.
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Baudet, Mathieu, Véronique Cortier, and Stéphanie Delaune. "YAPA." ACM Transactions on Computational Logic 14, no. 1 (2013): 1–32. http://dx.doi.org/10.1145/2422085.2422089.
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Feng, Shaojie, Chenghe Xiong, Guirong Wang, Subo Wang, Guoxia Jin, and Guofeng Gu. "Exploration of Recombinant Fusion Proteins YAPO and YAPL as Carrier Proteins for Glycoconjugate Vaccine Design against Streptococcus pneumoniae Infection." ACS Infectious Diseases 6, no. 8 (2020): 2181–91. http://dx.doi.org/10.1021/acsinfecdis.0c00260.
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Subramaniam, Aparna, Jing Zheng, Sudha Yalamanchili, et al. "Modulation of YAP/ TAZ by statins to improve survival in epithelioid hemangioendothelioma (EHE)." Journal of Clinical Oncology 38, no. 15_suppl (2020): e23527-e23527. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e23527.
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e23527 Background: EHE is a rare soft tissue tumor of endothelial origin. It is distinguished by the pathognomonic WWTR1-CAMTA1 fusion (WWTR1 is the gene symbol for TAZ) seen in 90% of the tumors. YAP1-TFE3 fusion is less common and seen in 10% of the tumors. YAP and TAZ are critical downstream effectors of the Hippo pathway that regulate tumor development, progression, invasion and metastasis by modulating the expression of many Hippo pathway targets. Recent studies have shown that inhibition of HMG-CoA reductase, a key enzyme of the mevalonate pathway, can regulate YAP/ TAZ by preventing their nuclear accumulation and inhibiting their transcriptional activity. This has led to interest in the role of statins, which inhibit HMG-CoA reductase, as a modulator of YAP/ TAZ that could benefit patients with sarcoma, particularly EHE. Methods: A retrospective analysis was performed on patients with a diagnosis of EHE at M D Anderson Cancer Center. Patients were identified using the electronic database system and screened for statin use using EMRs. Demographic and clinical characteristics were tabulated. KM method was used to assess overall survival and log rank test was used to test survival differences between the statin use and non- statin use groups. All statistical analysis was performed using STATA 14. Results: 226 patients with EHE were identified. 27 of them had recorded statin use during the course of their disease. The median OS for the statin use group was not reached and the mean OS was 221 months. The median OS for the non- statin use group was 123.9 months, while the mean OS was 160 months. The difference in OS was not statistically significant between the two groups. The median follow-up time for our cohort was 36.6 months. Conclusions: Our findings indicate a trend towards improved survival for patients with EHE who have received statins over the course of their disease. Our study is limited by a small number of patients who received statins. Prospective studies are required to assess the therapeutic benefit of statins in EHE. [Table: see text]
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Kawauchi, Daisuke, Kristian Pajtler, Yiju Wei, et al. "TB-06 MOLECULAR MECHANISM OF BRAIN TUMOUR FORMATION DRIVEN BY SUPRATENTORIAL EPENDYMOMA-SPECIFIC YAP1 FUSION GENES." Neuro-Oncology Advances 1, Supplement_2 (2019): ii11. http://dx.doi.org/10.1093/noajnl/vdz039.048.
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Abstract YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions but not YAP1 wildtype are sufficient to drive malignant transformation of neural progenitors in the developing cerebral cortex in mice, and the resulting tumours share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is associated with its oncogenicity and is mediated by the nuclear localization signal of MAMLD1 in a YAP1-Ser127 phosphorylation-independent manner. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, hypothesizing the important role of these transcription factors in YAP1-MAMLD1-driven tumourigenesis. Indeed, co-immunoprecipitation assays revealed physical interactions of TEADs and NFIA/B with the YAP1 and MAMLD1 domains of the fusion protein, respectively. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumour induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.
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Ben, Chi, Xiaojing Wu, Atsushi Takahashi-Kanemitsu, Christopher Takaya Knight, Takeru Hayashi, and Masanori Hatakeyama. "Alternative splicing reverses the cell-intrinsic and cell-extrinsic pro-oncogenic potentials of YAP1." Journal of Biological Chemistry 295, no. 41 (2020): 13965–80. http://dx.doi.org/10.1074/jbc.ra120.013820.
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In addition to acting as a transcriptional co-activator, YAP1 directly mediates translocalization of the pro-oncogenic phosphatase SHP2 from the cytoplasm to nucleus. In the cytoplasm, SHP2 potentiates RAS–ERK signaling, which promotes cell proliferation and cell motility, whereas in the nucleus, it mediates gene regulation. As a result, elucidating the details of SHP2 trafficking is important for understanding its biological roles, including in cancer. YAP1 comprises multiple splicing isoforms defined in part by the presence (as in YAP1-2γ) or absence (as in YAP1-2α) of a γ-segment encoded by exon 6 that disrupts a critical leucine zipper. Although the disruptive segment is known to reduce co-activator function, it is unclear how this element impacts the physical and functional relationships between YAP1 and SHP2. To explore this question, we first demonstrated that YAP1-2γ cannot bind SHP2. Nevertheless, YAP1-2γ exhibits stronger mitogenic and motogenic activities than does YAP1-2α because the YAP1-2α–mediated delivery of SHP2 to the nucleus weakens cytoplasmic RAS–ERK signaling. However, YAP1-2γ confers less in vivo tumorigenicity than does YA1-2α by recruiting tumor-inhibitory macrophages. Mechanistically, YAP1-2γ transactivates and the YAP1-2α–SHP2 complex transrepresses the monocyte/macrophage chemoattractant CCL2. Thus, cell-intrinsic and cell-extrinsic pro-oncogenic YAP1 activities are inversely regulated by alternative splicing of exon 6. Notably, oncogenic KRAS down-regulates the SRSF3 splicing factor that prevents exon 6 skipping, thereby creating a YAP1-2α–dominant situation that supports a “cold” immune microenvironment.
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Zeng, Cheng, Pei-Li Wu, Zhao-Tong Dong, Xin Li, Ying-Fang Zhou, and Qing Xue. "YAP1 inhibits ovarian endometriosis stromal cell invasion through ESR2." Reproduction 160, no. 3 (2020): 481–90. http://dx.doi.org/10.1530/rep-19-0565.
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Endometriosis is an estrogen-dependent disease, and estrogen receptor 2 (ESR2) plays a critical role in the pathogenesis of ovarian endometriosis by promoting cell invasion. Yes-associated protein 1 (YAP1) plays suppressive roles in several types of tumors. However, the relationship between YAP1 and ESR2 is not fully understood. The aim of this study was to investigate the regulatory mechanism of YAP1 in terms of ESR2 and YAP1 regulation of endometriotic stromal cell (ECSC) invasion in ovarian endometriosis. Our results demonstrated that YAP1 mRNA and protein levels in eutopic endometrium (EU) tissues were higher than those in paired ectopic endometrium (EC) tissues. ECSCs transfected with siYAP1 exhibited a significant increase in both ESR2 mRNA levels and protein expression. Simultaneously, YAP1 overexpression in ECSCs yielded the opposite results. Co-IP assays demonstrated YAP1-NuRD complex formation by YAP1, CHD4 and MTA1 in ECSCs. YAP1 bound to two sites, (-539, -533) and (-158, -152), upstream of the ESR2 transcription initiation site. YAP1 binding to the two sites of the ESR2 promoter in ECSCs was significantly lower than that in eutopic endometrial stromal cells (EUSCs) from EU tissues. ECSCs transfected with siYAP1 exhibited increased invasion activity, while ECSCs transfected with siESR2 showed inhibition of invasion. However, transfection with siYAP1 and siESR2 together decreased the number of invading cells compared with transfection with siYAP1 alone. Therefore, we conclude that decreased levels of YAP1 in ovarian endometriomas enhance ESR2 expression via formation of a YAP1-NuRD complex, which further binds to the ESR2 promoters. Furthermore, YAP1 inhibits ECSCs invasion.
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Qadir, Javeria, Syeda Kiran Riaz, Kiran Taj, et al. "Increased YAP1 expression is significantly associated with breast cancer progression, metastasis and poor survival." Future Oncology 17, no. 21 (2021): 2725–34. http://dx.doi.org/10.2217/fon-2020-1080.
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YAP1 plays a key role as a transcriptional coactivator in the Hippo pathway. Based on conflicting reports regarding YAP1 function in cancer, this study discerned its role in breast carcinogenesis. First, a systematic review of salient breast cancer studies targeting YAP1 dysregulation was performed. Additionally, freshly excised tumor specimens of approximately 200 breast cancer patients were processed for quantification of YAP1 expression at mRNA and protein levels using quantitative PCR and immunohistochemistry, respectively. YAP1 expression was nine folds higher in tumors versus controls and significantly associated with metastasis (p < 0.05) and poor survival in Pakistani breast cancer patients. These findings establish the role of YAP1 overexpression in tumorigenesis and metastasis. Hence, YAP1 inhibition may be considered a possible therapeutic strategy.
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Tang, Hao, Ping Gong, Ling Tao, and Yurong Hua. "miR-194 Inhibits Ovarian Cancer Cell Proliferation and Reduces Cisplatin Resistance by Targeting Yes-Associated Protein." Journal of Biomaterials and Tissue Engineering 10, no. 8 (2020): 1170–75. http://dx.doi.org/10.1166/jbt.2020.2379.
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Elevated expression of Yes-associated protein (YAP1) is associated with ovarian cancer. Bioinformatics analysis showed a relationship between miR-194 and YAP1. Our study intends to assess whether miR-194 regulates YAP1 expression and affects the proliferation of ovarian cancer cells and CDDP resistance. CDDP-resistant cell line A2780/CDDP was established and the expression of miR-194 and YAP1 in parental A2780 cells and normal ovarian epithelial IOSE80 cells were compared. A2780/CDDP cells were separated into miR-NC group and miR-194 mimic group followed by analysis of miR-194 and YAP1 expression, and cell apoptosis and proliferation by flow cytometry. There was a targeted relationship between miR-194 and YAP1 mRNA. A2780/CDDP cells had the lowest miR-194 expression followed by A2780 cells and IOSE80 cells. In addition, YAP1 level was highest in A2780/CDDP cells followed by A2780 cells and IOSE80 cells. Compared with miR-NC group, miR-194 expression was significantly increased in miR-194 mimic transfection group and YAP1 protein expression was significantly decreased, with increased cell apoptosis and reduced cell proliferation ability. Decreased miR-194 expression and increased YAP1 expression are related to ovarian cancer CDDP resistance. Increased miR-194 can down-regulate YAP1, inhibit ovarian cancer cell proliferation, promote cell apoptosis, and reduce CDDP resistance.