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1
Wijchers, Patrick J. E. C., J. Peter H. Burbach, and Marten P. Smidt. "In control of biology: of mice, men and Foxes." Biochemical Journal 397, no. 2 (June 28, 2006): 233–46. http://dx.doi.org/10.1042/bj20060387.
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Forkhead proteins comprise a highly conserved family of transcription factors, named after the original forkhead gene in Drosophila. To date, over 100 forkhead genes have been identified in a large variety of species, all sharing the evolutionary conserved ‘forkhead’ DNA-binding domain, and the cloning and characterization of forkhead genes have continued in recent years. Forkhead transcription factors regulate the expression of countless genes downstream of important signalling pathways in most, if not all, tissues and cell types. Recent work has provided novel insights into the mechanisms that contribute to their functional diversity, including functional protein domains and interactions of forkheads with other transcription factors. Studies using loss- and gain-of-function models have elucidated the role of forkhead factors in developmental biology and cellular functions such as metabolism, cell division and cell survival. The importance of forkhead transcription factors is underlined by the developmental defects observed in mutant model organisms, and multiple human disorders and cancers which can be attributed to mutations within members of the forkhead gene family. This review provides a comprehensive overview of current knowledge on forkhead transcription factors, from structural organization and regulatory mechanisms to cellular and developmental functions in mice and humans. Finally, we will discuss how novel insights gained from involvement of ‘Foxes’ in the mechanisms underlying human pathology may create new opportunities for treatment strategies.
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Carlsson, Peter, and Margit Mahlapuu. "Forkhead Transcription Factors: Key Players in Development and Metabolism." Developmental Biology 250, no. 1 (October 2002): 1–23. http://dx.doi.org/10.1006/dbio.2002.0780.
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Klotz. "FOXO Transcription Factors: Regulators of Metabolism and Stress Resistance." Proceedings 11, no. 1 (April 16, 2019): 11. http://dx.doi.org/10.3390/proceedings2019011011.
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FOXO (Forkhead box, class O) proteins are transcriptional regulators ubiquitously expressed in mammalian cells with roles in modulating fuel metabolism, stress resistance and cell death. FOXO transcription factors are regulated by redox processes at several levels, including enzymatic and nonenzymatic posttranslational modification. Target genes controlled by FOXO proteins include genes encoding antioxidant proteins, thus likely contributing to the key role FOXOs play in the cellular response to oxidative stress. Here, an overview is provided on (i) the modulation of FOXO proteins by thiol depleting agents, (ii) consequences of thiol depletion for stress resistance and life span of a model organism, Caenorhabditis elegans and (iii) the role of FOXO proteins therein.
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van der Heide, Lars P., Frank M. J. Jacobs, J. Peter H. Burbach, Marco F. M. Hoekman, and Marten P. Smidt. "FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling." Biochemical Journal 391, no. 3 (October 25, 2005): 623–29. http://dx.doi.org/10.1042/bj20050525.
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Forkhead members of the ‘O’ class (FoxO) are transcription factors crucial for the regulation of metabolism, cell cycle, cell death and cell survival. FoxO factors are regulated by insulin-mediated activation of PI3K (phosphoinositide 3-kinase)–PKB (protein kinase B) signalling. Activation of PI3K–PKB signalling results in the phosphorylation of FoxO factors on three conserved phosphorylation motifs, which are essential for the translocation of FoxO factors from the nucleus to the cytosol. FoxO6, however, remains mostly nuclear due to the fact that its shuttling ability is dramatically impaired. FoxO1, FoxO3 and FoxO4 all contain an N- and C-terminal PKB motif and a motif located in the forkhead domain. FoxO6 lacks the conserved C-terminal PKB motif, which is the cause of the shuttling impairment. Since FoxO6 can be considered constitutively nuclear, we investigated whether it is also a constitutively active transcription factor. Our results show that FoxO6 transcriptional activity is inhibited by growth factors, independent of shuttling, indicating that it is not constitutively active. The PKB site in the forkhead domain (Ser184) regulated the DNA binding characteristics and the N-terminal PKB site acted as a growth factor sensor. In summary, FoxO6 is not a constitutively active transcription factor and can be regulated by growth factors in a Thr26- and Ser184-dependent manner, independent of shuttling to the cytosol.
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Farhan, Mohd, Marta Silva, Xing Xingan, Yu Huang, and Wenhua Zheng. "Role of FOXO Transcription Factors in Cancer Metabolism and Angiogenesis." Cells 9, no. 7 (June 30, 2020): 1586. http://dx.doi.org/10.3390/cells9071586.
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Forkhead box O transcription factors (FOXOs) regulate several signaling pathways and play crucial roles in health and disease. FOXOs are key regulators of the expression of genes involved in multiple cellular processes and their deregulation has been implicated in cancer. FOXOs are generally considered tumor suppressors and evidence also suggests that they may have a role in the regulation of cancer metabolism and angiogenesis. In order to continue growing and proliferating, tumor cells have to reprogram their metabolism and induce angiogenesis. Angiogenesis refers to the process of new blood capillary formation from pre-existing vessels, which is an essential driving force in cancer progression and metastasis through supplying tumor cells with oxygen and nutrients. This review summarizes the roles of FOXOs in the regulation of cancer metabolism and angiogenesis. A deeper knowledge of the involvement of FOXOs in these two key processes involved in cancer dissemination may help to develop novel therapeutic approaches for cancer treatment.
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Wang, Yu, Yanmin Zhou, and Dana T. Graves. "FOXO Transcription Factors: Their Clinical Significance and Regulation." BioMed Research International 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/925350.
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Members of the class O of forkhead box transcription factors (FOXO) have important roles in metabolism, cellular proliferation, stress resistance, and apoptosis. The activity of FOXOs is tightly regulated by posttranslational modification, including phosphorylation, acetylation, and ubiquitylation. Activation of cell survival pathways such as phosphoinositide-3-kinase/AKT/IKK or RAS/mitogen-activated protein kinase phosphorylates FOXOs at different sites which regulate FOXOs nuclear localization or degradation. FOXO transcription factors are upregulated in a number of cell types including hepatocytes, fibroblasts, osteoblasts, keratinocytes, endothelial cells, pericytes, and cardiac myocytes. They are involved in a number of pathologic and physiologic processes that include proliferation, apoptosis, autophagy, metabolism, inflammation, cytokine expression, immunity, differentiation, and resistance to oxidative stress. These processes impact a number of clinical conditions such as carcinogenesis, diabetes, diabetic complications, cardiovascular disease, host response, and wound healing. In this paper, we focus on the potential role of FOXOs in different disease models and the regulation of FOXOs by various stimuli.
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Mondeel, Thierry D. G. A., Petter Holland, Jens Nielsen, and Matteo Barberis. "ChIP-exo analysis highlights Fkh1 and Fkh2 transcription factors as hubs that integrate multi-scale networks in budding yeast." Nucleic Acids Research 47, no. 15 (July 12, 2019): 7825–41. http://dx.doi.org/10.1093/nar/gkz603.
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AbstractThe understanding of the multi-scale nature of molecular networks represents a major challenge. For example, regulation of a timely cell cycle must be coordinated with growth, during which changes in metabolism occur, and integrate information from the extracellular environment, e.g. signal transduction. Forkhead transcription factors are evolutionarily conserved among eukaryotes, and coordinate a timely cell cycle progression in budding yeast. Specifically, Fkh1 and Fkh2 are expressed during a lengthy window of the cell cycle, thus are potentially able to function as hubs in the multi-scale cellular environment that interlocks various biochemical networks. Here we report on a novel ChIP-exo dataset for Fkh1 and Fkh2 in both logarithmic and stationary phases, which is analyzed by novel and existing software tools. Our analysis confirms known Forkhead targets from available ChIP-chip studies and highlights novel ones involved in the cell cycle, metabolism and signal transduction. Target genes are analyzed with respect to their function, temporal expression during the cell cycle, correlation with Fkh1 and Fkh2 as well as signaling and metabolic pathways they occur in. Furthermore, differences in targets between Fkh1 and Fkh2 are presented. Our work highlights Forkhead transcription factors as hubs that integrate multi-scale networks to achieve proper timing of cell division in budding yeast.
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van der HEIDE, Lars P., Marco F. M. HOEKMAN, and Marten P. SMIDT. "The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation." Biochemical Journal 380, no. 2 (June 1, 2004): 297–309. http://dx.doi.org/10.1042/bj20040167.
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FoxO (forkhead box O; forkhead members of the O class) are transcription factors that function under the control of insulin/insulin-like signalling. FoxO factors have been associated with a multitude of biological processes, including cell-cycle, cell death, DNA repair, metabolism and protection from oxidative stress. Central to the regulation of FoxO factors is a shuttling system, which confines FoxO factors to either the nucleus or the cytosol. Shuttling of FoxO requires protein phosphorylation within several domains, and association with 14-3-3 proteins and the nuclear transport machinery. Description of the FoxO-shuttling mechanism contributes to the understanding of FoxO function in relation to signalling and gene regulation.
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FOUFELLE, Fabienne, and Pascal FERRÉ. "New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c." Biochemical Journal 366, no. 2 (September 1, 2002): 377–91. http://dx.doi.org/10.1042/bj20020430.
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The regulation of hepatic glucose metabolism has a key role in whole-body energy metabolism, since the liver is able to store (glycogen synthesis, lipogenesis) and to produce (glycogenolysis, gluconeogenesis) glucose. These pathways are regulated at several levels, including a transcriptional level, since many of the metabolism-related genes are expressed according to the quantity and quality of nutrients. Recent advances have been made in the understanding of the regulation of hepatic glycolytic, lipogenic and gluconeogenic gene expression by pancreatic hormones, insulin and glucagon and glucose. Here we review the role of the transcription factors forkhead and sterol regulatory element binding protein-1c in the inductive and repressive effects of insulin on hepatic gene expression, and the pathway that leads from glucose to gene regulation with the recently discovered carbohydrate response element binding protein. We discuss how these transcription factors are integrated in a regulatory network that allows a fine tuning of hepatic glucose storage or production, and their potential importance in metabolic diseases.
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Murtaza, Ghulam, Abida Kalsoom Khan, Rehana Rashid, Saiqa Muneer, Syed Muhammad Farid Hasan, and Jianxin Chen. "FOXO Transcriptional Factors and Long-Term Living." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–8. http://dx.doi.org/10.1155/2017/3494289.
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Several pathologies such as neurodegeneration and cancer are associated with aging, which is affected by many genetic and environmental factors. Healthy aging conceives human longevity, possibly due to carrying the defensive genes. For instance, FOXO (forkhead box O) genes determine human longevity. FOXO transcription factors are involved in the regulation of longevity phenomenon via insulin and insulin-like growth factor signaling. Only one FOXO gene (FOXO DAF-16) exists in invertebrates, while four FOXO genes, that is, FOXO1, FOXO3, FOXO4, and FOXO6 are found in mammals. These four transcription factors are involved in the multiple cellular pathways, which regulate growth, stress resistance, metabolism, cellular differentiation, and apoptosis in mammals. However, the accurate mode of longevity by FOXO factors is unclear until now. This article describes briefly the existing knowledge that is related to the role of FOXO factors in human longevity.
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Ferré, P., D. Azzout-Marniche, and F. Foufelle. "AMP-activated protein kinase and hepatic genes involved in glucose metabolism." Biochemical Society Transactions 31, no. 1 (February 1, 2003): 220–23. http://dx.doi.org/10.1042/bst0310220.
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Mammalian AMP-activated protein kinase presents strong structural and functional similarities with the yeast sucrose non-fermenting 1 (Snf1) kinase involved in the derepression of glucose-repressed genes. It is now clearly established that AMP-activated protein kinase in the liver decreases glycolytic/lipogenic gene expression as well as genes involved in hepatic glucose production. This is achieved through a decreased transcriptional efficiency of transcription factors such as sterol-regulatory-element-binding protein-1c, carbohydrate-response-element-binding protein, hepatocyte nuclear factor 4α or forkhead-related protein. Clearly, the long-term consequences of AMP-activated protein kinase activation have to be taken into account if activators of this enzyme are to be designed as anti-diabetic drugs.
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Psenakova, Katarina, Klara Kohoutova, Veronika Obsilova, Michael Ausserlechner, Vaclav Veverka, and Tomas Obsil. "Forkhead Domains of FOXO Transcription Factors Differ in both Overall Conformation and Dynamics." Cells 8, no. 9 (August 24, 2019): 966. http://dx.doi.org/10.3390/cells8090966.
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FOXO transcription factors regulate cellular homeostasis, longevity and response to stress. FOXO1 (also known as FKHR) is a key regulator of hepatic glucose production and lipid metabolism, and its specific inhibition may have beneficial effects on diabetic hyperglycemia by reducing hepatic glucose production. Moreover, all FOXO proteins are considered potential drug targets for drug resistance prevention in cancer therapy. However, the development of specific FOXO inhibitors requires a detailed understanding of structural differences between individual FOXO DNA-binding domains. The high-resolution structure of the DNA-binding domain of FOXO1 reported in this study and its comparison with structures of other FOXO proteins revealed differences in both their conformation and flexibility. These differences are encoded by variations in protein sequences and account for the distinct functions of FOXO proteins. In particular, the positions of the helices H1, H2 and H3, whose interface form the hydrophobic core of the Forkhead domain, and the interactions between hydrophobic residues located on the interface between the N-terminal segment, the H2-H3 loop, and the recognition helix H3 differ among apo FOXO1, FOXO3 and FOXO4 proteins. Therefore, the availability of apo structures of DNA-binding domains of all three major FOXO proteins will support the development of FOXO-type-specific inhibitors.
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Maiese, Kenneth, Jinling Hou, Zhao Zhong Chong, and Yan Chen Shang. "A Fork in the Path: Developing Therapeutic Inroads with FoxO Proteins." Oxidative Medicine and Cellular Longevity 2, no. 3 (2009): 119–29. http://dx.doi.org/10.4161/oxim.2.3.8916.
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Advances in clinical care for disorders involving any system of the body necessitates novel therapeutic strategies that can focus upon the modulation of cellular proliferation, metabolism, inflammation and longevity. In this respect, members of the mammalian forkhead transcription factors of the O class (FoxOs) that include FoxO1, FoxO3, FoxO4 and FoxO6 are increasingly being recognized as exciting prospects for multiple disorders. These transcription factors govern development, proliferation, survival and longevity during multiple cellular environments that can involve oxidative stress. Furthermore, these transcription factors are closely integrated with several novel signal transduction pathways, such as erythropoietin and Wnt proteins, that may influence the ability of FoxOs to act as a “double-edge sword” to sometimes promote cell survival, but at other times lead to cell injury. Here we discuss the fascinating but complex role of FoxOs during cellular injury and oxidative stress, progenitor cell development, fertility, angiogenesis, cardiovascular function, cellular metabolism and diabetes, cell longevity, immune surveillance and cancer.
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Maiese, Kenneth, Zhao Zhong Chong, Yan Chen Shang, and Jinling Hou. "FoxO proteins: cunning concepts and considerations for the cardiovascular system." Clinical Science 116, no. 3 (January 8, 2009): 191–203. http://dx.doi.org/10.1042/cs20080113.
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Dysfunction in the cardiovascular system can lead to the progression of a number of disease entities that can involve cancer, diabetes, cardiac ischaemia, neurodegeneration and immune system dysfunction. In order for new therapeutic avenues to overcome some of the limitations of present clinical treatments for these disorders, future investigations must focus upon novel cellular processes that control cellular development, proliferation, metabolism and inflammation. In this respect, members of the mammalian forkhead transcription factors of the O class (FoxOs) have increasingly become recognized as important and exciting targets for disorders of the cardiovascular system. In the present review, we describe the role of these transcription factors in the cardiovascular system during processes that involve angiogenesis, cardiovascular development, hypertension, cellular metabolism, oxidative stress, stem cell proliferation, immune system regulation and cancer. Current knowledge of FoxO protein function combined with future studies should continue to lay the foundation for the successful translation of these transcription factors into novel and robust clinical therapies.
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Kodani, Noriko, and Jun Nakae. "Tissue-Specific Metabolic Regulation of FOXO-Binding Protein: FOXO Does Not Act Alone." Cells 9, no. 3 (March 13, 2020): 702. http://dx.doi.org/10.3390/cells9030702.
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The transcription factor forkhead box (FOXO) controls important biological responses, including proliferation, apoptosis, differentiation, metabolism, and oxidative stress resistance. The transcriptional activity of FOXO is tightly regulated in a variety of cellular processes. FOXO can convert the external stimuli of insulin, growth factors, nutrients, cytokines, and oxidative stress into cell-specific biological responses by regulating the transcriptional activity of target genes. However, how a single transcription factor regulates a large set of target genes in various tissues in response to a variety of external stimuli remains to be clarified. Evidence indicates that FOXO-binding proteins synergistically function to achieve tightly controlled processes. Here, we review the elaborate mechanism of FOXO-binding proteins, focusing on adipogenesis, glucose homeostasis, and other metabolic regulations in order to deepen our understanding and to identify a novel therapeutic target for the prevention and treatment of metabolic disorders.
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Jiramongkol, Yannasittha, and Eric W. F. Lam. "FOXO transcription factor family in cancer and metastasis." Cancer and Metastasis Reviews 39, no. 3 (May 5, 2020): 681–709. http://dx.doi.org/10.1007/s10555-020-09883-w.
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Abstract Forkhead box O (FOXO) transcription factors regulate diverse biological processes, affecting development, metabolism, stem cell maintenance and longevity. They have also been increasingly recognised as tumour suppressors through their ability to regulate genes essential for cell proliferation, cell death, senescence, angiogenesis, cell migration and metastasis. Mechanistically, FOXO proteins serve as key connection points to allow diverse proliferative, nutrient and stress signals to converge and integrate with distinct gene networks to control cell fate, metabolism and cancer development. In consequence, deregulation of FOXO expression and function can promote genetic disorders, metabolic diseases, deregulated ageing and cancer. Metastasis is the process by which cancer cells spread from the primary tumour often via the bloodstream or the lymphatic system and is the major cause of cancer death. The regulation and deregulation of FOXO transcription factors occur predominantly at the post-transcriptional and post-translational levels mediated by regulatory non-coding RNAs, their interactions with other protein partners and co-factors and a combination of post-translational modifications (PTMs), including phosphorylation, acetylation, methylation and ubiquitination. This review discusses the role and regulation of FOXO proteins in tumour initiation and progression, with a particular emphasis on cancer metastasis. An understanding of how signalling networks integrate with the FOXO transcription factors to modulate their developmental, metabolic and tumour-suppressive functions in normal tissues and in cancer will offer a new perspective on tumorigenesis and metastasis, and open up therapeutic opportunities for malignant diseases.
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Eelen, Guy, Els Vanoirbeek, Lieve Verlinden, Rik Gijsbers, Ine Beullens, Mark Van Camp, Ji-Hye Paik, Ronald DePinho, Roger Bouillon, and Annemieke Verstuyf. "Forkhead Box O (FoxO) Transcription Factors in the Actions of 1,25-Dihydroxyvitamin D3 on Osteoblasts." Bone 46 (March 2010): S48. http://dx.doi.org/10.1016/j.bone.2010.01.108.
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Fatima, Kaneez, Shilu Mathew, Muhammed Faheem, Tahir Mehmood, Hadi Mohamad Yassine, Asmaa A. Al Thani, Hany Abdel-Hafiz, Khalid Al Ghamdy, and Ishtiaq Qadri. "The Dual Specificity Role of Transcription Factor FOXO in Type 2-diabetes and Cancer." Current Pharmaceutical Design 24, no. 24 (November 8, 2018): 2839–48. http://dx.doi.org/10.2174/1381612824666180911114210.
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The FOXO (Forkhead box O) transcription factors are implicated in several signaling pathways and play a vital role in various cellular and physiological processes include for instance, ROS (reactive oxygen species) response, cell proliferation, regulation of programmed cell death, longevity, metabolism and cancer and regulation of cell cycle. In humans, the four FOXO family members are responsible for resemblance in their structure, regulation and functions. FOXO1 gene is highly expressed in adipose tissues and it affects the regulation of glycogenolysis and gluconeogenesis through insulin signaling. The gene of FOXO3 is highly expressed in the kidney, heart, spleen and brain and is characterized as diverse forkhead DNA-binding domain of transcription factors. The FOXO3 is a tumor suppressor gene and found to interact with p53, the trigger for apoptosis through BCl2 family genes and a regulator of Notch signaling pathway for the self-renewal of stem cells. Therefore, FOXOs remains to be a fascinating and potential target to acquire novel therapeutic approaches to cure cancer. This review will provide a comprehensive overview about the biology of FOXO proteins, which can be utilized for developing current therapeutic approaches to treat cancer.
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Senokuchi, T., C. P. Liang, T. A. Seimon, S. Han, M. Matsumoto, A. S. Banks, J. H. Paik, et al. "Forkhead Transcription Factors (FoxOs) Promote Apoptosis of Insulin-Resistant Macrophages During Cholesterol-Induced Endoplasmic Reticulum Stress." Diabetes 57, no. 11 (August 26, 2008): 2967–76. http://dx.doi.org/10.2337/db08-0520.
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Banerjee, Arup, Keith Meyer, Budhaditya Mazumdar, Ratna B. Ray, and Ranjit Ray. "Hepatitis C Virus Differentially Modulates Activation of Forkhead Transcription Factors and Insulin-Induced Metabolic Gene Expression." Journal of Virology 84, no. 12 (March 31, 2010): 5936–46. http://dx.doi.org/10.1128/jvi.02344-09.
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ABSTRACT Chronic hepatitis C virus (HCV) infection is often associated with insulin resistance and hepatic steatosis. Insulin regulates gene expression of key enzymes in glucose and lipid metabolism by modulating the activity of specific Forkhead box transcriptional regulators (FoxO1 and FoxA2) via the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway in the liver. In this study, we observed that HCV infection of human hepatocytes impaired insulin-induced FoxO1 translocation from the nucleus to the cytoplasm and significantly reduced accumulation of FoxA2 in the nucleus. Phosphorylation of FoxO1 at Ser256, a downstream target for Akt, was inhibited in hepatocytes infected with HCV or expressing the core protein or full-length (FL) genome of HCV. Further, an interaction between FoxO1 and 14-3-3 protein, important for FoxO1 translocation, was inhibited in HCV core-expressing cells. Hepatocytes infected with HCV, expressing the core protein alone or polyprotein displayed an increased level of glucose-6-phosphatase (G6P) mRNA. On the other hand, microsomal triglycerol transfer protein (MTP) activity and apolipoprotein B (ApoB) secretion were significantly reduced in hepatocytes expressing HCV proteins. Together, these observations suggest that HCV infection or ectopic expression of the core protein either alone or together with other viral proteins from an FL gene construct differentially modulates FoxO1 and FoxA2 activation and affects insulin-induced metabolic gene regulation in human hepatocytes.
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Nestal de Moraes, Gabriela, Luciana Carneiro, Raquel Maia, Eric Lam, and Andrew Sharrocks. "FOXK2 Transcription Factor and Its Emerging Roles in Cancer." Cancers 11, no. 3 (March 20, 2019): 393. http://dx.doi.org/10.3390/cancers11030393.
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Forkhead box (FOX) transcription factors compose a large family of regulators of key biological processes within a cell. FOXK2 is a member of FOX family, whose biological functions remain relatively unexplored, despite its description in the early nineties. More recently, growing evidence has been pointing towards a role of FOXK2 in cancer, which is likely to be context-dependent and tumour-specific. Here, we provide an overview of important aspects concerning the mechanisms of regulation of FOXK2 expression and function, as well as its complex interactions at the chromatin level, which orchestrate how it differentially regulates the expression of gene targets in pathophysiology. Particularly, we explore the emerging functions of FOXK2 as a regulator of a broad range of cancer features, such as cell proliferation and survival, DNA damage, metabolism, migration, invasion and metastasis. Finally, we discuss the prognostic value of assessing FOXK2 expression in cancer patients and how it can be potentially targeted for future anticancer interventions.
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Lam, Eric W.-F., Kunal Shah, and Jan J. Brosens. "The diversity of sex steroid action: the role of micro-RNAs and FOXO transcription factors in cycling endometrium and cancer." Journal of Endocrinology 212, no. 1 (March 7, 2011): 13–25. http://dx.doi.org/10.1530/joe-10-0480.
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The rise and fall in ovarian oestrogen and progesterone production orchestrates a series of events that are indispensable for reproduction, including ovulation, implantation, decidualisation and menstruation. In the uterus, these events involve extensive tissue remodelling, characterised by waves of endometrial cell proliferation, differentiation, recruitment of inflammatory cells, apoptosis, tissue breakdown, menstruation and regeneration. The ability of ovarian hormones to trigger such diverse physiological responses is foremost dependent upon interaction of activated steroid receptors with specific transcription factors, such as Forkhead box class O (FOXO) proteins, involved in cell fate decisions. Furthermore, micro-RNAs (miRNAs), small non-coding RNAs that function as posttranscriptional regulators of gene expression, have emerged as a major regulator system of steroid hormone responses in the female reproductive tract. Consequently, increasing evidence shows that deregulated uterine miRNA expression underpins a spectrum of common reproductive disorders, ranging from implantation failure to endometriosis. Furthermore, by targeting FOXO transcription factors and other key regulators of tissue homeostasis, oncogenic endometrial miRNAs promote tumourigenesis and cancer progression.
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Maiese, Kenneth, Jinling Hou, Zhao Zhong Chong, and Yan Chen Shang. "Erythropoietin, Forkhead Proteins, and Oxidative Injury: Biomarkers and Biology." Scientific World JOURNAL 9 (2009): 1072–104. http://dx.doi.org/10.1100/tsw.2009.121.
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Oxidative stress significantly impacts multiple cellular pathways that can lead to the initiation and progression of varied disorders throughout the body. It therefore becomes imperative to elucidate the components and function of novel therapeutic strategies against oxidative stress to further clinical diagnosis and care. In particular, both the growth factor and cytokine erythropoietin (EPO), and members of the mammalian forkhead transcription factors of the O class (FoxOs), may offer the greatest promise for new treatment regimens, since these agents and the cellular pathways they oversee cover a range of critical functions that directly influence progenitor cell development, cell survival and degeneration, metabolism, immune function, and cancer cell invasion. Furthermore, both EPO and FoxOs function not only as therapeutic targets, but also as biomarkers of disease onset and progression, since their cellular pathways are closely linked and overlap with several unique signal transduction pathways. Yet, EPO and FoxOs may sometimes have unexpected and undesirable effects that can raise caution for these agents and warrant further investigations. Here we present the exciting as well as the complex role that EPO and FoxOs possess to uncover the benefits as well as the risks of these agents for cell biology and clinical care in processes that range from stem cell development to uncontrolled cellular proliferation.
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Zhang, Kebin, Ling Li, Yajuan Qi, Xiaoping Zhu, Boyi Gan, Ronald A. DePinho, Travis Averitt, and Shaodong Guo. "Hepatic Suppression of Foxo1 and Foxo3 Causes Hypoglycemia and Hyperlipidemia in Mice." Endocrinology 153, no. 2 (February 1, 2012): 631–46. http://dx.doi.org/10.1210/en.2011-1527.
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Dysregulation of blood glucose and triglycerides are the major characteristics of type 2 diabetes mellitus. We sought to identify the mechanisms regulating blood glucose and lipid homeostasis. Cell-based studies established that the Foxo forkhead transcription factors Forkhead box O (Foxo)-1, Foxo3, and Foxo4 are inactivated by insulin via a phosphatidylinositol 3-kinase/Akt-dependent pathway, but the role of Foxo transcription factors in the liver in regulating nutrient metabolism is incompletely understood. In this study, we used the Cre/LoxP genetic approach to delete the Foxo1, Foxo3, and Foxo4 genes individually or a combination of two or all in the liver of lean or db/db mice and assessed the role of Foxo inactivation in regulating glucose and lipid homeostasis in vivo. In the lean mice or db/db mice, hepatic deletion of Foxo1, rather than Foxo3 or Foxo4, caused a modest reduction in blood glucose concentrations and barely affected lipid homeostasis. Combined deletion of Foxo1 and Foxo3 decreased blood glucose levels, elevated serum triglyceride and cholesterol concentrations, and increased hepatic lipid secretion and caused hepatosteatosis. Analysis of the liver transcripts established a prominent role of Foxo1 in regulating gene expression of gluconeogenic enzymes and Foxo3 in the expression of lipogenic enzymes. Our findings indicate that Foxo1 and Foxo3 inactivation serves as a potential mechanism by which insulin reduces hepatic glucose production and increases hepatic lipid synthesis and secretion in healthy and diabetic states.
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Jin, Yue, Zhangqian Liang, and Huiqiang Lou. "The Emerging Roles of Fox Family Transcription Factors in Chromosome Replication, Organization, and Genome Stability." Cells 9, no. 1 (January 20, 2020): 258. http://dx.doi.org/10.3390/cells9010258.
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The forkhead box (Fox) transcription factors (TFs) are widespread from yeast to humans. Their mutations and dysregulation have been linked to a broad spectrum of malignant neoplasias. They are known as critical players in DNA repair, metabolism, cell cycle control, differentiation, and aging. Recent studies, especially those from the simple model eukaryotes, revealed unexpected contributions of Fox TFs in chromosome replication and organization. More importantly, besides functioning as a canonical TF in cell signaling cascades and gene expression, Fox TFs can directly participate in DNA replication and determine the global replication timing program in a transcription-independent mechanism. Yeast Fox TFs preferentially recruit the limiting replication factors to a subset of early origins on chromosome arms. Attributed to their dimerization capability and distinct DNA binding modes, Fkh1 and Fkh2 also promote the origin clustering and assemblage of replication elements (replication factories). They can mediate long-range intrachromosomal and interchromosomal interactions and thus regulate the four-dimensional chromosome organization. The novel aspects of Fox TFs reviewed here expand their roles in maintaining genome integrity and coordinating the multiple essential chromosome events. These will inevitably be translated to our knowledge and new treatment strategies of Fox TF-associated human diseases including cancer.
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Zečić, Aleksandra, and Bart P. Braeckman. "DAF-16/FoxO in Caenorhabditis elegans and Its Role in Metabolic Remodeling." Cells 9, no. 1 (January 2, 2020): 109. http://dx.doi.org/10.3390/cells9010109.
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DAF-16, the only forkhead box transcription factors class O (FoxO) homolog in Caenorhabditis elegans, integrates signals from upstream pathways to elicit transcriptional changes in many genes involved in aging, development, stress, metabolism, and immunity. The major regulator of DAF-16 activity is the insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway, reduction of which leads to lifespan extension in worms, flies, mice, and humans. In C. elegans daf-2 mutants, reduced IIS leads to a heterochronic activation of a dauer survival program during adulthood. This program includes elevated antioxidant defense and a metabolic shift toward accumulation of carbohydrates (i.e., trehalose and glycogen) and triglycerides, and activation of the glyoxylate shunt, which could allow fat-to-carbohydrate conversion. The longevity of daf-2 mutants seems to be partially supported by endogenous trehalose, a nonreducing disaccharide that mammals cannot synthesize, which points toward considerable differences in downstream mechanisms by which IIS regulates aging in distinct groups.
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Westergren, Rickard, Daniel Nilsson, Mikael Heglind, Zahra Arani, Mats Grände, Anna Cederberg, Bo Ahrén, and Sven Enerbäck. "Overexpression of Foxf2 in adipose tissue is associated with lower levels of IRS1 and decreased glucose uptake in vivo." American Journal of Physiology-Endocrinology and Metabolism 298, no. 3 (March 2010): E548—E554. http://dx.doi.org/10.1152/ajpendo.00395.2009.
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Many members of the forkhead genes family of transcription factors have been implicated as important regulators of metabolism, in particular, glucose homeostasis, e.g., Foxo1, Foxa3, and Foxc2. The purpose of this study was to exploit the possibility that yet unknown members of this gene family play a role in regulating glucose tolerance in adipocytes. We identified Foxf2 in a screen for adipose-expressed forkhead genes. In vivo overexpression of Foxf2 in an adipose tissue-restricted fashion demonstrated that such mice display a significantly induced insulin secretion in response to an intravenous glucose load compared with wild-type littermates. In response to increased Foxf2 expression, insulin receptor substrate 1 (IRS1) mRNA and protein levels are significantly downregulated in adipocytes; however, the ratio of serine vs. tyrosine phosphorylation of IRS1 seems to remain unaffected. Furthermore, adipocytes overexpressing Foxf2 have a significantly lower insulin-mediated glucose uptake compared with wild-type adipocytes. These findings argue that Foxf2 is a previously unrecognized regulator of cellular and systemic whole body glucose tolerance, at least in part, due to lower levels of IRS1. Foxf2 and its downstream target genes can provide new insights with regard to identification of novel therapeutic targets.
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Hatta, Mitsutoki, and Lisa Ann Cirillo. "Chromatin Opening and Stable Perturbation of Core Histone:DNA Contacts by FoxO1." Journal of Biological Chemistry 282, no. 49 (October 8, 2007): 35583–93. http://dx.doi.org/10.1074/jbc.m704735200.
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FoxO1, a member of the forkhead rabdomyosarcoma (FoxO) subfamily of transcription factors, binds DNA via a highly conserved winged-helix “forkhead box” motif used by other regulatory proteins to mediate their effects through chromatin binding and remodeling. To examine how FoxO1 regulates target genes in chromatin, we studied the binding of purified recombinant FoxO1 protein to nucleosome particles and chromatin arrays containing the insulin-like growth factor-binding protein 1 promoter. We found that FoxO1 is able to bind to its cognate sites within the insulin-like growth factor-binding protein 1 promoter on a nucleosome. This binding stably perturbs core histone:DNA contacts extending up- and downstream from sites of FoxO1 binding without disrupting the underlying core particle. FoxO1 is able to harness these capabilities to bind to and de-condense linker histone-compacted chromatin arrays. Chromatin opening by FoxO1 requires both the N and C termini of the protein, which are also required for high affinity core histone binding and, in the case of the N terminus, nucleosome perturbation. We suggest that the chromatin binding and remodeling functions revealed here for FoxO1 endow all FoxO factors with the ability to initiate and dynamically modulate active chromatin states, enabling their diverse roles as gene regulatory factors in metabolism, cell survival, apoptosis, cell cycle progression, DNA repair, and protection against oxidative stress.
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Das, Pratyusa, Caitlin E. Stallings, and Buffy Sue Ellsworth. "Role of FOXO1 in Glucocorticoid-Induced Somatotrope Maturation." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A552—A553. http://dx.doi.org/10.1210/jendso/bvab048.1126.
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Abstract Growth hormone (GH) is a well-known metabolic factor secreted by pituitary somatotropes. Transcription factors such as POU1F1 and NEUROD4 promote somatotrope differentiation, maturation, and function. The forkhead transcription factor, FOXO1, is necessary for the proper timing of somatotrope differentiation and function, but the underlying mechanisms behind it have yet to be unraveled. Pituitary gland development also depends on regulation by signaling factors and hormones. Glucocorticoids have mixed effects on growth hormone production. However, when the effects of glucocorticoid signaling on the hypothalamus and pituitary gland are uncoupled, the direct effects of glucocorticoid signaling on pituitary somatotropes are not only stimulatory, but necessary for initiation of somatotrope maturation and for maintenance of somatotrope function. We find that FOXO1 is necessary for glucocorticoid induction of important somatotrope genes. Activation of glucocorticoid signaling in the somatotrope-derived MtT/S cell line induces transient expression of the bZIP transcription factor, Crebl2 within 2 hours. Interestingly, glucocorticoid induction of Crebl2 as well as the somatotrope genes Ghrhr and Gh1, is impaired in the presence of the FOXO1 inhibitor (AS1842856). There are several possible mechanisms underlying the requirement of FOXO1 in glucocorticoid induction of somatotrope maturation. One possible mechanism is that glucocorticoid signaling upregulates expression of Foxo1 and ultimately FOXO1 targets. Consistent with this possibility, Foxo1 expression is induced 8 hours after activation of glucocorticoid signaling. This does not appear to be the only mechanism underlying the role for FOXO1 in mediating glucocorticoid-induced somatotrope maturation, however, because many FOXO1 target genes, such as Neurod4 and Fosl2 are not affected by glucocorticoid signaling. We are currently investigating whether cooperative binding between FOXO1 and the glucocorticoid receptor contributes to transcriptional regulation of common targets genes. Together these data demonstrate that FOXO1 is a key factor mediating glucocorticoid induction of somatotrope maturation.
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Cheng, Alan, Mei Zhang, Sean M. Crosson, Zhao Q. Bao, and Alan R. Saltiel. "Regulation of the Mouse Protein Targeting to Glycogen (PTG) Promoter by the FoxA2 Forkhead Protein and by 3′,5′-Cyclic Adenosine 5′-Monophosphate in H4IIE Hepatoma Cells." Endocrinology 147, no. 7 (July 1, 2006): 3606–12. http://dx.doi.org/10.1210/en.2005-1513.
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The scaffolding protein, protein targeting to glycogen (PTG), orchestrates the signaling of several metabolic enzymes involved in glycogen synthesis. However, little is known concerning the regulation of PTG itself. In this study, we have cloned and characterized the mouse promoter of PTG. We identified multiple FoxA2 binding sites within this region. FoxA2 is a member of the forkhead family of transcription factors that has recently been implicated in the cAMP-dependent regulation of several genes involved in liver metabolism. Using luciferase reporter constructs, we demonstrate that FoxA2 transactivates the PTG promoter in H4IIE hepatoma cells. Nuclear extracts prepared from mouse liver and H4IIE cells were able to bind a FoxA2-specific probe derived within the PTG promoter region. Chromatin immunoprecipitation experiments further demonstrate that FoxA2 binds to the PTG promoter in vivo. Finally, we show that treatment with cAMP analogs activates the PTG promoter and significantly increases PTG levels in H4IIE cells. Our results provide a framework to investigate how additional transcription factors may regulate PTG expression in other cell types.
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Luo, Junqiu, Daiwen Chen, and Bing Yu. "Effects of different dietary protein sources on expression of genes related to protein metabolism in growing rats." British Journal of Nutrition 104, no. 10 (July 8, 2010): 1421–28. http://dx.doi.org/10.1017/s000711451000231x.
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Protein metabolism is known to be affected by dietary proteins, but the fundamental mechanisms that underlie the changes in protein metabolism are unclear. The aim of the present study was to test the effects of feeding growing rats with balanced diets containing soya protein isolate, zein and casein as the sole protein source on the expression of genes related to protein metabolism responses in skeletal muscle. The results showed that feeding a zein protein diet to the growing rats induced changes in protein anabolic and catabolic metabolism in their gastrocnemius muscles when compared with those fed either the reference protein casein diet or the soya protein isolate diet. The zein protein diet increased not only the mRNA levels and phosphorylation of mammalian target of rapamycin (mTOR), but also the mRNA expression of muscle atrophy F-box (MAFbx)/atrogin-1 and muscle ring finger 1 (MuRF1), as well as the forkhead box-O (FoxO) transcription factors involved in the induction of the E3 ligases. The amino acid profile of proteins seems to control signalling pathways leading to changes in protein synthesis and proteolysis.
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Eelen, G., C. Maes, C. Gysemans, J. H. Paik, R. DePinho, R. Bouillon, G. Carmeliet, and A. Verstuyf. "Severe growth plate abnormalities and increased bone volume in mice with chondrocyte-specific inactivation of Forkhead Box O (FOXO) transcription factors." Bone 48 (May 2011): S68. http://dx.doi.org/10.1016/j.bone.2011.03.063.
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Rozance, Paul J., Sean W. Limesand, James S. Barry, Laura D. Brown, Stephanie R. Thorn, Dan LoTurco, Timothy R. H. Regnault, Jacob E. Friedman, and William W. Hay. "Chronic late-gestation hypoglycemia upregulates hepatic PEPCK associated with increased PGC1α mRNA and phosphorylated CREB in fetal sheep." American Journal of Physiology-Endocrinology and Metabolism 294, no. 2 (February 2008): E365—E370. http://dx.doi.org/10.1152/ajpendo.00639.2007.
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Hepatic glucose production is normally activated at birth but has been observed in response to experimental hypoglycemia in fetal sheep. The cellular basis for this process remains unknown. We determined the impact of 2 wk of fetal hypoglycemia during late gestation on enzymes responsible for hepatic gluconeogenesis, focusing on the insulin-signaling pathway, transcription factors, and coactivators that regulate gluconeogenesis. Hepatic phospho enolpyruvate carboxykinase and glucose-6-phosphatase mRNA increased 12-fold and 7-fold, respectively, following chronic hypoglycemia with no change in hepatic glycogen. Chronic hypoglycemia decreased fetal plasma insulin with no change in glucagon but increased plasma cortisol 3.5-fold. Peroxisome proliferator-activated receptor-γ coactivator-1α mRNA and phosphorylation of cAMP response element binding protein at Ser133 were both increased, with no change in Akt, forkhead transcription factor FoxO1, hepatocyte nuclear factor-4α, or CCAAT enhancer binding protein-β. These results demonstrate that chronic fetal hypoglycemia triggers signals that can activate gluconeogenesis in the fetal liver.
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Stefanetti, Renae J., Sarah Voisin, Aaron Russell, and Séverine Lamon. "Recent advances in understanding the role of FOXO3." F1000Research 7 (August 31, 2018): 1372. http://dx.doi.org/10.12688/f1000research.15258.1.
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The forkhead box O3 (FOXO3, or FKHRL1) protein is a member of the FOXO subclass of transcription factors. FOXO proteins were originally identified as regulators of insulin-related genes; however, they are now established regulators of genes involved in vital biological processes, including substrate metabolism, protein turnover, cell survival, and cell death. FOXO3 is one of the rare genes that have been consistently linked to longevity in in vivo models. This review provides an update of the most recent research pertaining to the role of FOXO3 in (i) the regulation of protein turnover in skeletal muscle, the largest protein pool of the body, and (ii) the genetic basis of longevity. Finally, it examines (iii) the role of microRNAs in the regulation of FOXO3 and its impact on the regulation of the cell cycle.
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Watt, M. J., R. J. Southgate, A. G. Holmes, and M. A. Febbraio. "Suppression of plasma free fatty acids upregulates peroxisome proliferator-activated receptor (PPAR) α and δ and PPAR coactivator 1α in human skeletal muscle, but not lipid regulatory genes." Journal of Molecular Endocrinology 33, no. 2 (October 2004): 533–44. http://dx.doi.org/10.1677/jme.1.01499.
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Fatty acids are an important ligand for peroxisome proliferator-activated receptor (PPAR) activation and transcriptional regulation of metabolic genes. To examine whether reduced plasma free fatty acid (FFA) availability affects the mRNA content of proteins involved in fuel metabolism in vivo, the skeletal muscle mRNA content of various transcription factors, transcriptional coactivators and genes encoding for lipid regulatory proteins were examined before and after 3 h of cycle exercise with (NA) and without (CON) pre-exercise ingestion of nicotinic acid (NA). NA resulted in a marked (3- to 6-fold) increase (P<0.05) in PPARα, PPARδ and PPAR coactivator 1α (PGC1α) mRNA, but was without effect on nuclear respiratory factor-1 and Forkhead transcription factor, fatty acid transcolase/CD36, carnitine palmitoyl transferase 1, hormone sensitive lipase (HSL) and pyruvate dehydrogenase kinase 4. Exercise in CON was associated with increased (P<0.05) PPARα, PPARδ and PGC1α mRNA, which was similar in magnitude to levels observed with NA at rest. Exercise was generally without effect on the mRNA content of lipid regulatory proteins in CON and did not affect the mRNA content of the measured subset of transcription factors, transcriptional co-activators and lipid regulatory proteins during NA. To determine the possible mechanisms by which NA might affect PGC1α expression, we measured p38 MAP kinase (MAPK) and plasma epinephrine. Phosphorylation of p38 MAPK was increased (P<0.05) by NA treatment at rest, and this correlated (r2=0.84, P<0.01) with increased PGC1α. Despite this close relationship, increasing p38 MAPK in human primary myotubes was without effect on PGC1α mRNA content. Plasma epinephrine was elevated (P<0.05) by NA at rest (CON: 0.27±0.06, NA: 0.72±0.11 nM) and throughout exercise. Incubating human primary myotubes with epinephrine increased PGC1α independently of changes in p38 MAPK phosphorylation. Hence, despite the fact that NA ingestion decreased FFA availability, it promoted the induction of PPARα/δ and PGC1α gene expression to a similar degree as prolonged exercise. We suggest that the increase in PGC1α may be due to the elevated plasma epinephrine levels. Despite these changes in transcription factors/coactivators, the mRNA content of lipid regulatory proteins was generally unaffected by plasma FFA availability.
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Boonsaen, Thirajit, Pinnara Rojvirat, Kathy H. Surinya, John C. Wallace, and Sarawut Jitrapakdee. "Transcriptional regulation of the distal promoter of the rat pyruvate carboxylase gene by hepatocyte nuclear factor 3β/Foxa2 and upstream stimulatory factors in insulinoma cells." Biochemical Journal 405, no. 2 (June 27, 2007): 359–67. http://dx.doi.org/10.1042/bj20070276.
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PC (pyruvate carboxylase) plays a crucial role in intermediary metabolism including glucose-induced insulin secretion in pancreatic islets. In the present study, we identified two regions of the 1.2 kb distal promoter, the −803/−795 site and the −408/−403 E-box upstream of the transcription start site, as the important cis-acting elements for transcriptional activation of the luciferase reporter gene. Site-directed mutagenesis of either one of these sites in the context of this 1.2 kb promoter fragment, followed by transient transfections in the insulinoma cell line, INS-1, abolished reporter activity by approx. 50%. However, disruption of either the −803/−795 or the −408/−403 site did not affect reporter gene activity in NIH 3T3 cells, suggesting that this promoter fragment is subjected to cell-specific regulation. The nuclear proteins that bound to these −803/−795 and −408/−403 sites were identified by gel retardation assays as HNF3β (hepatocyte nuclear factor 3β)/Foxa2 (forkhead/winged helix transcription factor box2) and USFs (upstream stimulatory factors), USF1 and USF2, respectively. Chromatin immunoprecipitation assays using antisera against HNF3β/Foxa2, USF1 and USF2 demonstrated that endogenous HNF3β/Foxa2 binds to the −803/−795 Foxa2 site, and USF1 and USF2 bind to the −408/−403 E-box respectively in vivo, consistent with the gel retardation assay results. Although there are weak binding sites located at regions −904 and −572 for PDX1 (pancreatic duodenal homeobox-1), a transcription factor that controls expression of β-cell-specific genes, it did not appear to regulate PC expression in INS-1 cells in the context of the 1.2 kb promoter fragment. The results presented here show that Foxa2 and USFs regulate the distal promoter of the rat PC gene in a cell-specific manner.
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Nerurkar, Pratibha V., Adrienne Nishioka, Philip O. Eck, Lisa M. Johns, Esther Volper, and Vivek R. Nerurkar. "Regulation of glucose metabolism via hepatic forkhead transcription factor 1 (FoxO1) by Morinda citrifolia (noni) in high-fat diet-induced obese mice." British Journal of Nutrition 108, no. 2 (October 20, 2011): 218–28. http://dx.doi.org/10.1017/s0007114511005563.
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Renewed interest in alternative medicine among diabetic individuals prompted us to investigate anti-diabetic effects of Morinda citrifolia (noni) in high-fat diet (HFD)-fed mice. Type 2 diabetes is associated with increased glucose production due to the inability of insulin to suppress hepatic gluconeogenesis and promote glycolysis. Insulin inhibits gluconeogenesis by modulating transcription factors such as forkhead box O (FoxO1). Based on microarray analysis data, we tested the hypothesis that fermented noni fruit juice (fNJ) improves glucose metabolism via FoxO1 phosphorylation. C57BL/6 male mice were fed a HFD and fNJ for 12 weeks. Body weights and food intake were monitored daily. FoxO1 expression was analysed by real-time PCR and Western blotting. Specificity of fNJ-associated FoxO1 regulation of gluconeogenesis was confirmed by small interfering RNA (siRNA) studies using human hepatoma cells, HepG2. Supplementation with fNJ inhibited weight gain and improved glucose and insulin tolerance and fasting glucose in HFD-fed mice. Hypoglycaemic properties of fNJ were associated with the inhibition of hepatic FoxO1 mRNA expression, with a concomitant increase in FoxO1 phosphorylation and nuclear expulsion of the proteins. Gluconeogenic genes, phosphoenolpyruvate C kinase (PEPCK) and glucose-6-phosphatase (G6P), were significantly inhibited in mice fed a HFD+fNJ. HepG2 cells demonstrated more than 80 % inhibition of PEPCK and G6P mRNA expression in cells treated with FoxO1 siRNA and fNJ. These data suggest that fNJ improves glucose metabolism via FoxO1 regulation in HFD-fed mice.
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Mattila, Jaakko, Anna Bremer, Linda Ahonen, Risto Kostiainen, and Oscar Puig. "Drosophila FoxO Regulates Organism Size and Stress Resistance through an Adenylate Cyclase." Molecular and Cellular Biology 29, no. 19 (August 3, 2009): 5357–65. http://dx.doi.org/10.1128/mcb.00302-09.
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ABSTRACT Forkhead box class O (FoxO) transcription factors are a family of conserved proteins that regulate the cellular responses to various stimuli, such as energy deprivation, stress, and developmental cues. FoxO proteins are important mediators of the insulin signaling pathway, adjusting growth and metabolism to nutrient availability. Insulin signaling acts together with the glucagon-stimulated cAMP signaling pathway to orchestrate the organism response to various nutritional conditions. In this study, we demonstrate that Drosophila melanogaster FoxO (dFoxO) regulates cAMP signaling by directly inducing the expression of an adenylate cyclase gene, ac76e. Interestingly, ac76e is expressed in a highly restricted pattern throughout fly development, limited to the corpus allatum (CA), gastric cecum, and malpighian tubules. dFoxO activation of AC76E in the CA increases starvation resistance and limits growth. Our results unravel a new role for dFoxO, integrating cAMP and insulin signaling to adapt organism growth to the existing nutritional conditions.
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Laha, Anwesha, Mahavir Singh, Akash K. George, Rubens P. Homme, and Suresh C. Tyagi. "Dysregulation of 1-carbon metabolism and muscle atrophy: potential roles of forkhead box O proteins and PPARγ co-activator-1α." Canadian Journal of Physiology and Pharmacology 97, no. 11 (November 2019): 1013–17. http://dx.doi.org/10.1139/cjpp-2019-0227.
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Homocysteine, a non-proteinogenic amino acid but an important metabolic intermediate is generated as an integral component for the “1-carbon metabolism” during normal physiology. It is catabolized to cysteine via the transulfuration pathway resulting in the generation of hydrogen sulfide, a naturally endogenous byproduct. Genetics or metabolic derangement can alter homocysteine concentration leading to hyperhomocysteinemia (HHcy), a physiologically unfavorable condition that causes serious medical conditions including muscle wasting. HHcy environment can derail physiological processes by targeting biomolecules such as Akt; however, not much is known regarding the effects of HHcy on regulation of transcription factors such as forkhead box O (FOXO) proteins. Recently, hydrogen sulfide has been shown to be highly effective in alleviating the effects of HHcy by serving as an antiapoptotic factor, but role of FOXO and its interaction with hydrogen sulfide are yet to be established. In this review, we discuss role(s) of HHcy in skeletal muscle atrophy and how HHcy interact with FOXO and peroxisome proliferator-activated receptor gamma coactivator 1-alpha expressions that are relevant in musculoskeletal atrophy. Further, therapeutic intervention with hydrogen sulfide for harnessing its beneficial effects might help mitigate the dysregulated 1-carbon metabolism that happens to be the hallmark of HHcy-induced pathologies such as muscle atrophy.
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Kelleher, Andrew M., Francesco J. DeMayo, and Thomas E. Spencer. "Uterine Glands: Developmental Biology and Functional Roles in Pregnancy." Endocrine Reviews 40, no. 5 (May 10, 2019): 1424–45. http://dx.doi.org/10.1210/er.2018-00281.
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Abstract All mammalian uteri contain glands in the endometrium that develop only or primarily after birth. Gland development or adenogenesis in the postnatal uterus is intrinsically regulated by proliferation, cell–cell interactions, growth factors and their inhibitors, as well as transcription factors, including forkhead box A2 (FOXA2) and estrogen receptor α (ESR1). Extrinsic factors regulating adenogenesis originate from other organs, including the ovary, pituitary, and mammary gland. The infertility and recurrent pregnancy loss observed in uterine gland knockout sheep and mouse models support a primary role for secretions and products of the glands in pregnancy success. Recent studies in mice revealed that uterine glandular epithelia govern postimplantation pregnancy establishment through effects on stromal cell decidualization and placental development. In humans, uterine glands and, by inference, their secretions and products are hypothesized to be critical for blastocyst survival and implantation as well as embryo and placental development during the first trimester before the onset of fetal–maternal circulation. A variety of hormones and other factors from the ovary, placenta, and stromal cells impact secretory function of the uterine glands during pregnancy. This review summarizes new information related to the developmental biology of uterine glands and discusses novel perspectives on their functional roles in pregnancy establishment and success.
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Masuyama, Hisashi, and Yuji Hiramatsu. "Potential role of estradiol and progesterone in insulin resistance through constitutive androstane receptor." Journal of Molecular Endocrinology 47, no. 2 (July 18, 2011): 229–39. http://dx.doi.org/10.1530/jme-11-0046.
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Normal pregnancy is characterized by insulin resistance, which contributes to the development of gestational diabetes mellitus and preeclampsia by incompletely understood mechanisms. The constitutive androstane receptor (CAR) may participate in insulin resistance in pregnancy, and sex steroids, estradiol (E2) and progesterone, may also be involved. We applied glucose and insulin tolerance tests and measured the expression of gluconeogenic and lipogenic genes in the livers of oophorectomized mice treated with E2 and progesterone with or without CAR ligands. We also investigated how E2 and progesterone affected CAR-mediated signaling and the activity of transcription factors in gluconeogenesis in vitro. Mice with the concentrations of E2 and progesterone within normal physiological range during pregnancy exhibited increased insulin resistance along with increased expression of gluconeogenic and lipogenic genes, and CAR activation rescued the abnormal glucose metabolism. In HepG2 cells, CAR ligands suppressed the gluconeogenic and lipogenic gene expression in the presence of E2 and/or progesterone. DNA affinity immunoblotting and chromatin immunoprecipitation assay revealed that CAR ligand enhanced the recruitment of the gluconeogenic transcription factors, forkhead box O1 (FOXO1) and hepatocyte nuclear factor 4α (HNF4α), but sex steroids suppressed these recruitments on the CAR responsive element. Moreover, CAR ligand suppressed the recruitment of FOXO1 and HNF4α on their responsive element in gluconeogenic gene promoters and E2 and progesterone augmented these recruitments on their responsive element. Taken together, these findings suggest that the activation of CAR-mediated signaling may ameliorate insulin resistance under relatively high concentrations of E2 and progesterone, which were compatible with pregnancy via decreased activities of transcription factors in gluconeogenesis in combination with CAR.
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Manolagas, Stavros C., and Maria Almeida. "Gone with the Wnts: β-Catenin, T-Cell Factor, Forkhead Box O, and Oxidative Stress in Age-Dependent Diseases of Bone, Lipid, and Glucose Metabolism." Molecular Endocrinology 21, no. 11 (November 1, 2007): 2605–14. http://dx.doi.org/10.1210/me.2007-0259.
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Abstract The Wnt/β-catenin signaling pathway affects several biological processes ranging from embryonic development, patterning, and postembryonic stem cell fate, to bone formation and insulin secretion in adulthood. β-Catenin mediates canonical Wnt signaling by binding to and activating members of the T-cell factor (TCF) transcription factor family. Similar to the Wnt/β-catenin pathway, oxidative stress influences fundamental cellular processes including stem cell fate and has been linked to aging and the development of age-related diseases. However, the molecular details of the pathogenetic effects of oxidative stress on the homeostasis of many different tissues remain unclear. β-Catenin has been recently implicated as a pivotal molecule in defense against oxidative stress by serving as a cofactor of the forkhead box O (FOXO) transcription factors. In addition, it has been shown that oxidative stress is a pivotal pathogenetic factor of age-related bone loss and strength in mice, leading to, among other changes, a decrease in osteoblast number and bone formation. These particular cellular changes evidently result from diversion of the limited pool of β-catenin from TCF- to FOXO-mediated transcription in osteoblastic cells. Fascinatingly, attenuation of Wnt-mediated transcription, resulting from an autosomal-dominant missense mutation in LRP6, a coreceptor for the Wnt-signaling pathway, has been linked recently genetically not only to premature osteoporosis, but also to coronary artery disease as well as several features of the metabolic syndrome including hyperlipidemia, hypertension, and diabetes, but not obesity. In this minireview, we highlight evidence linking the age-associated oxidative stress with FOXOs, Wnt/β-catenin signaling, osteoblastogenesis, adipogenesis, osteoporosis, and several features of the metabolic syndrome. We hypothesize that antagonism of Wnt signaling by oxidative stress with increasing age may be a common molecular mechanism contributing to the development not only of involutional osteoporosis, but several pathologies such as atherosclerosis, insulin resistance, and hyperlipidemia, all of which become more prevalent with advancing age.
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Marmorstein, R. "Structure and chemistry of the Sir2 family of NAD+-dependent histone/protein deactylases." Biochemical Society Transactions 32, no. 6 (October 26, 2004): 904–9. http://dx.doi.org/10.1042/bst0320904.
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The yeast Sir2 (silent information regulator-2) protein functions as an NAD+-dependent histone deacetylase to silence gene expression from the mating-type locus, tolomeres and rDNA and also promotes longevity and genome stability in response to calorie restriction. Homologues of yeast Sir2 have been identified in the three domains of bacteria, archaea and eukaryotes; in mammalian cells, Sir2 proteins also deacetylate non-histone proteins such as the p53 tumour suppressor protein, α-tubulin and forkhead transcription factors to mediate diverse biological processes including metabolism, cell motility and cancer. We have determined the X-ray crystal structure of a Sir2 homologue from yeast Hst2 (yHst2), in various liganded forms, including the yHst2/acetyl-Lys-16 histone H4/NAD+ ternary complex; we have also performed related biochemical studies to address the conserved mode of catalysis by these enzymes as well as the distinguishing features that allow different members of the family to target their respective cognate substrates. These studies have implications for the structure-based design of Sir2-specific small molecule compounds, which might modulate Sir2 function for therapeutic application.
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Camilletti, Maria Andrea, Sebastian Vishnopolska, María Florencia Mercogliano, Amanda Helen Mortensen, Augusto Chaves Murriello, Debora Giselle Braslavsky, Ana Claudia Keselman, et al. "Identification of FOXA2 and PNPLA6 Among Other Genes, as a Potential Risk for Pituitary Hormone Deficiency." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A540—A541. http://dx.doi.org/10.1210/jendso/bvab048.1101.
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Abstract Pituitary hormone deficiency or hypopituitarism is characterized by a malformed or underdeveloped pituitary gland resulting in an impaired pituitary hormone secretion. Several transcription factors have been described in its etiology, but defects in known genes account for only a small proportion of cases. We sought to identify the cause of hypopituitarism in 171 unrelated patients diagnosed with or without extra-pituitary manifestations that were recruited from several Argentinean medical centers. We conducted panel sequencing, and identified among other genes and variants, de novo heterozygous mutations in FOXA2 and PNPLA6. FOXA2 is a transcription factor member of the forkhead class of DNA-binding proteins, involved in the early development of multiple tissues. FOXA2 is highly expressed throughout the developing hypothalamic-pituitary axis, and regulates GLI2, SHH and NKX2-2 expression. Mutations of FOXA2 have been linked to combined pituitary hormone deficiency (CPHD) in some cases with extra-pituitary phenotypes including hyperinsulinism or gastrointestinal malformations. We found two patients with CPHD and rare FOXA2 variants. Case 1 had GHD, anterior pituitary hypoplasia, mammary hypertelorism and digital anomalies and a heterozygous variant FOXA2 p.Arg228Ser, predicted to be pathogenic. Case 2 had GH and TSH deficiency, craniofacial anomalies and neurodevelopmental delay, and a novel, stop codon mutation FOXA2 p.Ser229* and an heterozygous GLI1 variant (p.Asp1048Asn). Both FOXA2 variants are located within the forkhead domain which may affect the DNA binding ability. We suspect they are likely damaging based on the literature, the in-silico prediction, and their absence in GnomAD. PNPLA6 is a conserved lysophospholipase involved in maintaining nervous system integrity. Mutations in PNPLA6 have been identified in a broad spectrum from pure ataxia to rare neuroendocrine conditions including Gordon Holmes and Oliver McFarlane syndromes. Here, we identified two de novo heterozygous variants in PNPLA6 in children with CPHD. Variant p.W1039R was found in a patient with CPHD, intellectual disability and visual problems. A second variant (p.T1115P) was identified in a 10-year-old girl with CPHD, retinitis pigmentosa and neurodevelopmental delay. According to modelling studies of the protein structure, both variants are expected to be critical for the activity of the NTE as they are located in close proximity to the protein’s catalytic pocket. It is likely that these variants may contribute to our patient’s phenotype. However, as most reported PNPLA6 variants in the literature were found in homozygosity or compound heterozygosity, additional studies are necessary to draw more definitive genotype-phenotype correlations. In summary, in this work we were able to expand our knowledge of pituitary target genes for genetic diagnosis for CH.
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Xiong, Xiwen, Rongya Tao, Ronald A. DePinho, and X. Charlie Dong. "The Autophagy-related Gene 14 (Atg14) Is Regulated by Forkhead Box O Transcription Factors and Circadian Rhythms and Plays a Critical Role in Hepatic Autophagy and Lipid Metabolism." Journal of Biological Chemistry 287, no. 46 (September 19, 2012): 39107–14. http://dx.doi.org/10.1074/jbc.m112.412569.
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Puthanveetil, Prasanth, Ying Wang, Fang Wang, Min Suk Kim, Ashraf Abrahani, and Brian Rodrigues. "The Increase in Cardiac Pyruvate Dehydrogenase Kinase-4 after Short-Term Dexamethasone Is Controlled by an Akt-p38-Forkhead Box Other Factor-1 Signaling Axis." Endocrinology 151, no. 5 (February 24, 2010): 2306–18. http://dx.doi.org/10.1210/en.2009-1072.
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Glucocorticoids increase pyruvate dehydrogenase kinase-4 (PDK4) mRNA and protein expression, which phosphorylates pyruvate dehydrogenase, thereby preventing the formed pyruvate from undergoing mitochondrial oxidation. This increase in PDK4 expression is mediated by the mandatory presence of Forkhead box other factors (FoxOs) in the nucleus. In the current study, we examined the importance of the nongenomic effects of dexamethasone (Dx) in determining the compartmentalization of FoxO and hence its transcriptional activity. Rat cardiomyocytes exposed to Dx produced a robust decrease in glucose oxidation. Measurement of FoxO compartmentalization demonstrated increase in nuclear but resultant decrease in cytosolic content of FoxO1 with no change in the total content. The increase in nuclear content of FoxO1 correlated to an increase in nuclear phospho-p38 MAPK together with a robust association between this transcription factor and kinase. Dx also promoted nuclear retention of FoxO1 through a decrease in phosphorylation of Akt, an effect mediated by heat shock proteins binding to Akt. Measurement of the nuclear and total expression of sirtuin-1 protein showed no change after Dx. Instead, Dx increased the association of sirtuin-1 with FoxO1, thereby causing a decrease in FoxO acetylation. Manipulation of FoxO1 through agents that interfere with its nuclear shuttling or acetylation were effective in reducing Dx-induced increase in PDK4 protein expression. Our data suggest that FoxO1 has a major PDK4-regulating function. In addition, given the recent suggestions that altering glucose use can set the stage for heart failure, manipulating FoxO could assist in devising new therapeutic strategies to optimize cardiac metabolism and prevent PDK4 induced cardiac complications.
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Imae, M., Y. Inoue, Z. Fu, H. Kato, and T. Noguchi. "Gene expression of the three members of hepatocyte nuclear factor-3 is differentially regulated by nutritional and hormonal factors." Journal of Endocrinology 167, no. 1 (October 1, 2000): R1—R5. http://dx.doi.org/10.1677/joe.0.167r001.
Full textAbstract:
Hepatocyte nuclear factor-3 (HNF-3) belongs to a large family of forkhead transcription factors and is made up of three members (HNF-3alpha, -3beta and -3gamma). It has been shown that HNF-3 regulates a number of metabolically important genes. However, the mechanisms underlying this regulation of HNF-3 activity by hormones and nutrition have not yet been well elucidated. In attempting to explore the regulation of gene expression of HNF-3 members by physiological status, we analyzed the effects of insulin, dexamethasone and protein malnutrition on the hepatic mRNA level of each member. Male Wistar rats were fed on a 12% casein diet, 12% gluten diet (deficient in lysine and threonine) or a protein-free diet for 1 week. The protein-free diet and gluten diet caused a 3. 7-fold increase in HNF-3g mRNA in the liver and did not affect the mRNA level of either HNF-3alpha or HNF-3beta. Daily administration of dexamethasone caused the mRNA levels of HNF-3alpha and HNF-3beta to increase (2.3- and 1.4-fold, respectively), but had no effect on the HNF-3gamma mRNA level. In diabetic rats that had been injected with streptozotocin, an elevation of the hepatic mRNA levels of HNF-3beta and HNF-3gamma was observed (1.6-and 1.9-fold, respectively). Insulin replacement in the diabetic rats decreased both mRNA levels in a dose-dependent manner. HNF-3alpha mRNA was not affected by insulin status. These results show that the genes of the three members of the HNF-3 family respond differently to hormonal and nutritional factors suggesting that the activities of HNF-3 members are regulated, at least in part, by the levels of their gene expression.
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Daitoku, Hiroaki, Yuta Kaneko, Kenji Yoshimochi, Kaori Matsumoto, Sho Araoi, Jun-ichi Sakamaki, Yuta Takahashi, and Akiyoshi Fukamizu. "Nontranscriptional Function of FOXO1/DAF-16 Contributes to Translesion DNA Synthesis." Molecular and Cellular Biology 36, no. 21 (August 22, 2016): 2755–66. http://dx.doi.org/10.1128/mcb.00265-16.
Full textAbstract:
Forkhead box O (FOXO; DAF-16 in nematodes) transcription factors activate a program of genes that control stress resistance, metabolism, and life span. Given the adverse impact of the stochastic DNA damage on organismal development and aging, we examined the role of FOXO/DAF-16 in UV-induced DNA damage response. Knockdown of FOXO1 but not of FOXO3a increases sensitivity to UV irradiation when exposed during S phase, suggesting a contribution of FOXO1 to translesion DNA synthesis (TLS), a replicative bypass of UV-induced DNA lesions. Actually, FOXO1 depletion results in sustained activation of ATR-Chk1 signaling and a reduction of proliferating cell nuclear antigen (PCNA) monoubiquitination following UV irradiation. FOXO1 does not alter the expression of TLS-related genes, but it binds to replication protein A 1 (RPA1), which coats single-stranded DNA and acts as a scaffold for TLS. InCaenorhabditis elegans,daf-16-null mutants show UV-induced retardation in larval development and are rescued by overexpressing a DAF-16 mutant lacking the transactivation domain but not a mutant whose amino acid substitutions render it unable to interact with RPA1. Thus, our findings demonstrate that FOXO1/DAF-16 is a functional component in TLS independent of its transactivation activity.
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Geiger, Kathrin, Judith Hagenbuchner, Martina Rupp, Heidi Fiegl, Consolato Sergi, Bernhard Meister, Ursula Kiechl-Kohlendorfer, Thomas Müller, Michael J. Ausserlechner, and Petra Obexer. "FOXO3/FKHRL1 is activated by 5-aza-2-deoxycytidine and induces silenced caspase-8 in neuroblastoma." Molecular Biology of the Cell 23, no. 11 (June 2012): 2226–34. http://dx.doi.org/10.1091/mbc.e11-06-0535.
Full textAbstract:
Forkhead box O (FOXO) transcription factors control diverse cellular functions, such as cell death, metabolism, and longevity. We analyzed FOXO3/FKHRL1 expression and subcellular localization in tumor sections of neuroblastoma patients and observed a correlation between nuclear FOXO3 and high caspase-8 expression. In neuroblastoma caspase-8 is frequently silenced by DNA methylation. Conditional FOXO3 activated caspase-8 gene expression but did not change the DNA-methylation pattern of regulatory sequences in the caspase-8 gene. Instead, FOXO3 induced phosphorylation of its binding partner ATM and of the ATM downstream target cAMP-responsive element binding protein (CREB), which was critical for FOXO3-mediated caspase-8 expression. Caspase-8 levels above a critical threshold sensitized neuroblastoma cells to tumor necrosis factor–related apoptosis-inducing ligand–induced cell death. The DNA-demethylating drug 5-Aza-2-deoxycytidine (5-azadC) induced rapid nuclear accumulation of FOXO3, ATM-dependent CREB phosphorylation, and caspase-8 expression in a FOXO3-dependent manner. This indicates that 5-azadC activates the FOXO3-ATM-CREB signaling pathway, which contributes to caspase-8 expression. The combined data suggest that FOXO3 is activated by 5-azadC treatment and triggers expression of caspase-8 in caspase-8–negative neuroblastoma, which may have important implication for metastasis, therapy, and death resistance of this childhood malignancy.
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Paik, J. H. "FOXOs in the maintenance of vascular homoeostasis." Biochemical Society Transactions 34, no. 5 (October 1, 2006): 731–34. http://dx.doi.org/10.1042/bst0340731.
Full textAbstract:
The mammalian FoxO (forkhead box O) transcription factors FoxO1, FoxO3 and FoxO4 represent one of several effector arms of the PI3K (phosphoinositide 3-kinase)–Akt signalling network that has been linked to cancer, metabolism and aging. Specific roles of the FoxOs in the vascular cell types have been investigated to reveal that they play redundant yet critical roles in the proliferation and survival of ECs (endothelial cells). Somatic deletions of all FoxOs engendered progressive, widespread and highly penetrant haemangiomas associated with altered proliferative/survival dynamics of ECs in our genetic model. Related work by Akt–FoxO manipulation reported differentially regulated genes in ECs that may represent novel FoxO targets, controlling EC growth and morphogenesis and mediating many of the consequences of FoxO inactivation in the endothelium. Further studies on the action of these surrogate genes may provide important new insights into how the PI3K–Akt–FoxO pathway could be exploited clinically to treat vascular diseases and lead to the invention of novel therapeutic approaches. Here recent studies elucidating the role of FoxOs in the maintenance of vascular homoeostasis and supporting that the mammalian FoxO family serves essential roles in the maintenance of vascular stability and the suppression of aberrant vascular outgrowth are discussed.