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• W4306857344 abstract "The pancreatic and duodenal homeobox 1 (PDX1) is a central regulator of glucose-dependent transcription of insulin in pancreatic β cells. PDX1 transcription factor activity is integral to the development and sustained health of the pancreas; accordingly, deciphering the complex network of cellular cues that lead to PDX1 activation or inactivation is an important step toward understanding the etiopathologies of pancreatic diseases and the development of novel therapeutics. Despite nearly 3 decades of research into PDX1 control of Insulin expression, the molecular mechanisms that dictate the function of PDX1 in response to glucose are still elusive. The transcriptional activation functions of PDX1 are regulated, in part, by its two intrinsically disordered regions, which pose a barrier to its structural and biophysical characterization. Indeed, many studies of PDX1 interactions, clinical mutations, and posttranslational modifications lack molecular level detail. Emerging methods for the quantitative study of intrinsically disordered regions and refined models for transactivation now enable us to validate and interrogate the biochemical and biophysical features of PDX1 that dictate its function. The goal of this review is to summarize existing PDX1 studies and, further, to generate a comprehensive resource for future studies of transcriptional control via PDX1. The pancreatic and duodenal homeobox 1 (PDX1) is a central regulator of glucose-dependent transcription of insulin in pancreatic β cells. PDX1 transcription factor activity is integral to the development and sustained health of the pancreas; accordingly, deciphering the complex network of cellular cues that lead to PDX1 activation or inactivation is an important step toward understanding the etiopathologies of pancreatic diseases and the development of novel therapeutics. Despite nearly 3 decades of research into PDX1 control of Insulin expression, the molecular mechanisms that dictate the function of PDX1 in response to glucose are still elusive. The transcriptional activation functions of PDX1 are regulated, in part, by its two intrinsically disordered regions, which pose a barrier to its structural and biophysical characterization. Indeed, many studies of PDX1 interactions, clinical mutations, and posttranslational modifications lack molecular level detail. Emerging methods for the quantitative study of intrinsically disordered regions and refined models for transactivation now enable us to validate and interrogate the biochemical and biophysical features of PDX1 that dictate its function. The goal of this review is to summarize existing PDX1 studies and, further, to generate a comprehensive resource for future studies of transcriptional control via PDX1. The pancreatic and duodenal homeobox 1 (PDX1) (also known as GSF (1Marshak S. Totary H. Cerasi E. Melloul D. Purification of the beta-cell glucose-sensitive factor that transactivates the insulin gene differentially in normal and transformed islet cells.Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 15057-15062Crossref PubMed Scopus (153) Google Scholar), IDX-1 (2Miller C.P. McGehee Jr., R.E. Habener J.F. IDX-1: A new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene.EMBO J. 1994; 13: 1145-1156Crossref PubMed Scopus (378) Google Scholar), IPF1 (3Ohlsson H. Karlsson K. Edlund T. IPF1, a homeodomain-containing transactivator of the insulin gene.EMBO J. 1993; 12: 4251-4259Crossref PubMed Scopus (772) Google Scholar), IUF (4MacFarlane W.M. Read M.L. Gilligan M. Bujalska I. Docherty K. Glucose modulates the binding activity of the beta-cell transcription factor IUF1 in a phosphorylation-dependent manner.Biochem. J. 1994; 303: 625-631Crossref PubMed Google Scholar), and STF-1 (5Peers B. Leonard J. Sharma S. Teitelman G. Montminy M.R. Insulin expression in pancreatic-islet cells relies on cooperative interactions between the helix-loop-helix factor E47 and the homeobox factor stf-1.Mol. Endocrinol. 1994; 8: 1798-1806PubMed Google Scholar)) is the central activator of glucose-dependent insulin transcription in pancreatic β cells (4MacFarlane W.M. Read M.L. Gilligan M. Bujalska I. Docherty K. Glucose modulates the binding activity of the beta-cell transcription factor IUF1 in a phosphorylation-dependent manner.Biochem. J. 1994; 303: 625-631Crossref PubMed Google Scholar). The PDX1 gene is located at chromosome 13q12.1 in Homo sapiens and at 5qG3 in Mus musculus (mouse); unless otherwise specified; discussion herein will focus on the H. sapiens protein PDX1. In addition to its role in developmentally mature organisms, PDX1 is of particular importance in the early differentiation of gut endoderm cells into pancreatic progenitors and, subsequently, the formation of insulin-producing cell mass (6Kim S.K. Hebrok M. Intercellular signals regulating pancreas development and function.Genes Dev. 2001; 15: 111-127Crossref PubMed Scopus (343) Google Scholar). Impaired expression or certain mutations of PDX1 during embryonic development are linked to pancreatic agenesis and the onset of diabetes with age (7Ahlgren U. Jonsson J. Jonsson L. Simu K. Edlund H. beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes.Genes Dev. 1998; 12: 1763-1768Crossref PubMed Google Scholar, 8Jonsson J. Carlsson L. Edlund T. Edlund H. Insulin-promoter-factor 1 is required for pancreas development in mice.Nature. 1994; 371: 606-609Crossref PubMed Scopus (1562) Google Scholar, 9Stoffers D.A. Zinkin N.T. Stanojevic V. Clarke W.L. Habener J.F. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence.Nat. Genet. 1997; 15: 106-110Crossref PubMed Scopus (926) Google Scholar, 10Schwitzgebel V.M. Mamin A. Brun T. Ritz-Laser B. Zaiko M. Maret A. et al.Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1.J. Clin. Endocrinol. Metab. 2003; 88: 4398-4406Crossref PubMed Scopus (151) Google Scholar). PDX1 is one of several transcription factors that direct development of pancreatic progenitor cells into the α, β, δ, and ε cells of the islets of Langerhans (11Babu D.A. Deering T.G. Mirmira R.G. A feat of metabolic proportions: pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis.Mol. Genet. Metab. 2007; 92: 43-55Crossref PubMed Scopus (0) Google Scholar) (Fig. 1A; for a thorough review about the different islet cell types, we refer the interested reader to reference (12Da Silva Xavier G. The cells of the islets of langerhans.J. Clin. Med. Res. 2018; 7: 1-17Google Scholar)). Importantly, PDX1 supports phenotypic maintenance of β cells, which enables glucose-stimulated insulin secretion throughout the organism’s lifetime (13Wilding L. Gannon M. The role of pdx1 and HNF6 in proliferation and differentiation of endocrine precursors.Diabetes Metab. Res. Rev. 2004; 20: 114-123Crossref PubMed Scopus (21) Google Scholar, 14Gao T. McKenna B. Li C. Reichert M. Nguyen J. Singh T. et al.Pdx1 maintains beta cell identity and function by repressing an alpha cell program.Cell Metab. 2014; 19: 259-271Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar). To this end, PDX1 plays a repressive role in β cells by downregulating non-β cell genes (15Ritz-Laser B. Gauthier B.R. Estreicher A. Mamin A. Brun T. Ris F. et al.Ectopic expression of the beta-cell specific transcription factor Pdx1 inhibits glucagon gene transcription.Diabetologia. 2003; 46: 810-821Crossref PubMed Scopus (42) Google Scholar, 16Teo A.K. Tsuneyoshi N. Hoon S. Tan E.K. Stanton L.W. Wright C.V. et al.PDX1 binds and represses hepatic genes to ensure robust pancreatic commitment in differentiating human embryonic stem cells.Stem Cell Rep. 2015; 4: 578-590Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). In addition, chromatin immunoprecipitation (ChIP) sequencing experiments using different islet cell types identified a strikingly similar PDX1 genomic distribution in β and δ cell (17Zhong F. Jiang Y. Endogenous pancreatic beta cell regeneration: a potential strategy for the recovery of beta cell deficiency in diabetes.Front. Endocrinol. 2019; 10: 1-14Crossref PubMed Scopus (35) Google Scholar, 18DiGruccio M.R. Mawla A.M. Donaldson C.J. Noguchi G.M. Vaughan J. Cowing-Zitron C. et al.Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets.Mol. Metab. 2016; 5: 449-458Crossref PubMed Scopus (195) Google Scholar). In this review, we focus on PDX1 control of Insulin transcription but acknowledge its many and diverse regulatory roles in pancreatic health and disease. In developmentally mature organisms, PDX1 expression is primarily localized to β cells. Notably, even among the β cells in a given islet, PDX1 expression is variable across transcriptionally mature and immature cells. This heterogeneity is important for glucose-stimulated insulin secretion and metabolism by the collective β cell population (19Nasteska D. Fine N.H.F. Ashford F.B. Cuozzo F. Viloria K. Smith G. et al.PDX1(LOW) MAFA(LOW) beta-cells contribute to islet function and insulin release.Nat. Commun. 2021; 12: 674Crossref PubMed Scopus (11) Google Scholar, 20Benninger R.K.P. Kravets V. The physiological role of β-cell heterogeneity in pancreatic islet function.Nat. Rev. Endocrinol. 2022; 18: 9-22Crossref PubMed Scopus (13) Google Scholar). PDX1 regulates the expression of insulin and other hormones in the pancreas such as somatostatin, glucokinase, glucose transporter type 1/3 (Glut1/3), and islet amyloid polypeptide (21Andersen F.G. Jensen J. Heller R.S. Petersen H.V. Larsson L.I. Madsen O.D. et al.Pax6 and Pdx1 form a functional complex on the rat somatostatin gene upstream enhancer.FEBS Lett. 1999; 445: 315-320Crossref PubMed Scopus (0) Google Scholar, 22Watada H. Kajimoto Y. Miyagawa J. Hanafusa T. Hamaguchi K. Matsuoka T. et al.PDX-1 induces insulin and glucokinase gene expressions in alpha-TCl clone 6 cells in the presence of betacellulin.Diabetes. 1996; 45: 1826-1831Crossref PubMed Google Scholar, 23Macfarlane W.M. Campbell S.C. Elrick L.J. Oates V. Bermano G. Lindley K.J. et al.Glucose regulates islet amyloid polypeptide gene transcription in a PDX1- and calcium-dependent manner.J. Biol. Chem. 2000; 275: 15330-15335Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 24Waeber G. Thompson N. Nicod P. Bonny C. Transcriptional activation of the GLUT2 gene by the IPF-1/STF-1/IDX-1 homeobox factor.Mol. Endocrinol. 1996; 10: 1327-1334Crossref PubMed Scopus (325) Google Scholar, 25Boam D.S.W. Docherty K. A tissue-specific nuclear factor binds to multiple sites in the human insulin-gene enhancer.Biochem. J. 1989; 264: 233-239Crossref PubMed Scopus (68) Google Scholar). However, given the importance of insulin in the function of β cells and the abundance of studies to this end, PDX1 control of INS transcription will be the focus of this review. While not the specific focus of this review, glucose sensing and insulin secretion by the β cell are inherently related to PDX1 action; accordingly, we provide a high level summary of these β cell processes. Briefly, Glut1/3 mediates glucose transport into the β cell, after which the glucose is processed by glycolysis in the cytoplasm and through the Krebs cycle in the mitochondria. The resulting increase of cytoplasmic ATP concentration blocks potassium efflux, leading to a change in membrane polarization that ultimately stimulates exocytosis of insulin granules (26Rutter G.A. Georgiadou E. Martinez-Sanchez A. Pullen T.J. Metabolic and functional specialisations of the pancreatic beta cell: Gene disallowance, mitochondrial metabolism and intercellular connectivity.Diabetologia. 2020; 63: 1990-1998Crossref PubMed Scopus (27) Google Scholar, 27Merrins M.J. Corkey B.E. Kibbey R.G. Prentki M. Metabolic cycles and signals for insulin secretion.Cell Metab. 2022; 34: 947-968Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) (Fig. 1B, top). Increased insulin in response to glucose stimulus is primarily a consequence of translation of proinsulin mRNA, thus replenishing the cell’s insulin stores (28Uchizono Y. Alarcón C. Wicksteed B.L. Marsh B.J. Rhodes C.J. The balance between proinsulin biosynthesis and insulin secretion: Where can imbalance lead?.Diabetes Obes. Metab. 2007; 9: 56-66Crossref PubMed Scopus (66) Google Scholar). In contrast to our deep and evolving understanding of glucose-stimulated insulin secretion, the specific mechanisms that lead to PDX1 activation are incomplete. In stimulating glucose conditions, PDX1 and other transcription factors localize to the nucleus and together activate transcription of INS mRNA (29Docherty H.M. Hay C.W. Ferguson L.A. Barrow J. Durward E. Docherty K. Relative contribution of PDX-1, MafA and E47/beta2 to the regulation of the human insulin promoter.Biochem. J. 2005; 389: 813-820Crossref PubMed Scopus (78) Google Scholar, 30Thomsen S.K. Gloyn A.L. The pancreatic beta cell: Recent insights from human genetics.Trends Endocrinol. Metab. 2014; 25: 425-434Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 31Stanojevic V. Habener J.F. Thomas M.K. Pancreas duodenum homeobox-1 transcriptional activation requires interactions with p300.Endocrinology. 2004; 145: 2918-2928Crossref PubMed Scopus (0) Google Scholar, 32Wu H. Macfarlane W.M. Tadayyon M. Arch J.R.S. James R.F.L. Docherty K. Insulin stimulates pancreatic–duodenal homoeobox factor-1 (PDX1) DNA- binding activity and insulin promoter activity in pancreatic β cells.Biochem. J. 1999; 344: 813-818Crossref PubMed Scopus (0) Google Scholar). On the other hand, low glucose conditions halt insulin secretion and inhibit PDX1-driven transcriptional activation (33Fu Z. Gilbert E.R. Liu D. Regulation of insulin synthesis and secretion and pancreatic beta-cell dysfunction in diabetes.Curr. Diabetes Rev. 2013; 9: 25-53Crossref PubMed Scopus (485) Google Scholar, 34Liu A. Desai B.M. Stoffers D.A. Identification of PCIF1, a POZ domain protein that inhibits PDX-1 (MODY4) transcriptional activity.Mol. Cell. Biol. 2004; 24: 4372-4383Crossref PubMed Scopus (50) Google Scholar) (Fig. 1B, bottom). To gain insight into how PDX1 orchestrates INS transcription, we must first interrogate the many reported PDX1 interactions and modifications associated with its activating function. In addition to cooperatively folded DNA-binding domains (DBDs), transcription factors tend to contain intrinsically disordered transactivation domains (TADs) that support interaction with posttranslational modification (PTM) enzymes, chromatin remodelers, transcriptional coactivators or repressor proteins, and other transcription factors (35Lazo P.A. Reverting p53 activation after recovery of cellular stress to resume with cell cycle progression.Cell. Signal. 2017; 33: 49-58Crossref PubMed Scopus (27) Google Scholar, 36Wang F. Marshall C.B. Yamamoto K. Li G.Y. Gasmi-Seabrook G.M. Okada H. et al.Structures of KIX domain of CBP in complex with two FOXO3a transactivation domains reveal promiscuity and plasticity in coactivator recruitment.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 6078-6083Crossref PubMed Scopus (76) Google Scholar, 37De Mol E. Szulc E. Di Sanza C. Martinez-Cristobal P. Bertoncini C.W. Fenwick R.B. et al.Regulation of androgen receptor activity by transient interactions of its transactivation domain with general transcription regulators.Structure. 2018; 26: 145-152Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 38Spaeth J.M. Walker E.M. Stein R. Impact of Pdx1-associated chromatin modifiers on islet beta-cells.Diabetes Obes. Metab. 2016; 18: 123-127Crossref PubMed Scopus (24) Google Scholar, 39Deering T.G. Ogihara T. Trace A.P. Maier B. Mirmira R.G. Methyltransferase Set7/9 maintains transcription and euchromatin structure at islet-enriched genes.Diabetes. 2009; 58: 185-193Crossref PubMed Scopus (95) Google Scholar, 40Staby L. O’Shea C. Willemoes M. Theisen F. Kragelund B.B. Skriver K. Eukaryotic transcription factors: Paradigms of protein intrinsic disorder.Biochem. J. 2017; 474: 2509-2532Crossref PubMed Scopus (78) Google Scholar). Intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs) are central regulators of protein function in nearly all cellular processes but are especially enriched in signaling and transcription-associated processes (41Xie H. Vucetic S. Iakoucheva L.M. Oldfield C.J. Dunker A.K. Uversky V.N. et al.Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions.J. Proteome Res. 2006; 6: 1882-1898Crossref Scopus (442) Google Scholar, 42Xue B. Dunker A.K. Uversky V.N. Orderly order in protein intrinsic disorder distribution: Disorder in 3500 proteomes from viruses and the three domains of life.J. Biomol. Struct. Dyn. 2012; 30: 137-149Crossref PubMed Scopus (389) Google Scholar). Up to 95% of eukaryotic transcription factors contain IDRs of >30 residues compared to up to 55% in control, nontranscription factor proteins (43Liu J. Perumal N.B. Oldfield C.J. Su E.W. Uversky V.N. Dunker A.K. Intrinsic disorder in transcription factors.Biochemistry. 2006; 45: 6873-6888Crossref PubMed Scopus (521) Google Scholar). Although IDRs lack stable folded structures, conformational plasticity poises them for interaction with multiple and/or functionally diverse binding partners; consequently, understanding IDR intermolecular interactions in the context of cellular function and health requires evaluating their solution ensembles with high spatial and temporal precision (36Wang F. Marshall C.B. Yamamoto K. Li G.Y. Gasmi-Seabrook G.M. Okada H. et al.Structures of KIX domain of CBP in complex with two FOXO3a transactivation domains reveal promiscuity and plasticity in coactivator recruitment.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 6078-6083Crossref PubMed Scopus (76) Google Scholar, 44Uversky V.N. Intrinsic disorder, protein-protein interactions, and disease.Adv. Protein Chem. Struct. Biol. 2018; 110: 85-121Crossref PubMed Scopus (69) Google Scholar, 45Mollica L. Bessa L.M. Hanoulle X. Jensen M.R. Blackledge M. Schneider R. Binding mechanisms of intrinsically disordered proteins: theory, simulation, and experiment.Front Mol. Biosci. 2016; 3: 1-18Crossref PubMed Scopus (78) Google Scholar). This is the exact paradox—the need to quantitatively describe structure in the context of pervasive disorder—that has impeded molecular characterization of transactivation function of transcription factors. Many IDR interactions are tailored by their covalent modification in or near a binding surface; such modification may be coupled to conformational consequences, but this is not universally required (46Arai M. Sugase K. Dyson H.J. Wright P.E. Conformational propensities of intrinsically disordered proteins influence the mechanism of binding and folding.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 9614-9619Crossref PubMed Scopus (168) Google Scholar, 47Phillips A.H. Kriwacki R.W. Intrinsic protein disorder and protein modifications in the processing of biological signals.Curr. Opin. Struct. Biol. 2019; 60: 1-6Crossref PubMed Scopus (8) Google Scholar). Due to their solvent accessibility and relative enrichment in modifiable amino acids, IDRs are frequently the subjects of PTMs in the pursuit of further functional regulation (48Bah A. Forman-Kay J.D. Modulation of intrinsically disordered protein function by post-translational modifications.J. Biol. Chem. 2016; 291: 6696-6705Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar). As will be discussed in the following sections of this review, several PDX1 interactions are maintained through IDRs and PDX1 PTMs tend to cluster in or near known interaction sites (see Table 1, Table 3). As such, the unstructured regions of PDX1 are valuable targets of study toward understanding basic mechanism and potential therapeutic strategies.Table 1Proteins reported to directly associate with PDX1 for the regulation of glucose-stimulated insulin transcription and their roles in INS regulationFactorOntologyReported function with PDX1PDX1 AAs for interactionConditionRef.β2aE47 (aka E2A) and β2 (aka NeuroD1) form a heterodimer (often called E47/β2) to bind E-box elements; E47/β2 also interacts with p300.bHLH TFBinds E-box motifsaE47 (aka E2A) and β2 (aka NeuroD1) form a heterodimer (often called E47/β2) to bind E-box elements; E47/β2 also interacts with p300. & Pdx1 via bHLH domain138–213 (HD)HG(95Ohneda K. Mirmira R.G. Wang J. Johnson J.D. German M.S. The homeodomain of PDX-1 mediates multiple protein-protein interactions in the formation of a transcriptional activation complex on the insulin promoter.Mol. Cell. Biol. 2000; 20: 900-911Crossref PubMed Scopus (168) Google Scholar, 195Glick E. Leshkowitz D. Walker M.D. Transcription factor BETA2 acts cooperatively with E2A and PDX1 to activate the insulin gene promoter.J. Biol. Chem. 2000; 275: 2199-2204Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar)Brg1bBrg1 and Brm incorporation into Swi/Snf is mutually exclusive.:Swi/SnfATPaseRemodels chromatin for promoter accessibilityNSHG(75McKenna B. Guo M. Reynolds A. Hara M. Stein R. Dynamic recruitment of functionally distinct Swi/Snf chromatin remodeling complexes modulates Pdx1 activity in islet beta cells.Cell Rep. 2015; 10: 2032-2042Abstract Full Text Full Text PDF PubMed Google Scholar)Bridge-1eBridge-1 was cloned from the INS-1 (rat insulinoma) cell line; PSMD9 is the human homolog.PDZ-domain coactivatorBinds Pdx1 and E2A to enhance INS activation1–63HG(100Thomas M.K. Yao K.M. Tenser M.S. Wong G.G. Habener J.F. Bridge-1, a novel PDZ-domain coactivator of E2A-mediated regulation of insulin gene transcription.Mol. Cell. Biol. 1999; 19: 8492-8504Crossref PubMed Google Scholar, 101Stanojevic V. Yao K.M. Thomas M.K. The coactivator Bridge-1 increases transcriptional activation by pancreas duodenum homeobox-1 (PDX-1).Mol. Cell. Endocrinol. 2005; 237: 67-74Crossref PubMed Scopus (0) Google Scholar)BrmbBrg1 and Brm incorporation into Swi/Snf is mutually exclusive.:Swi/SnfATPaseRepresses INS activation by heterochromatin formationNSLG(75McKenna B. Guo M. Reynolds A. Hara M. Stein R. Dynamic recruitment of functionally distinct Swi/Snf chromatin remodeling complexes modulates Pdx1 activity in islet beta cells.Cell Rep. 2015; 10: 2032-2042Abstract Full Text Full Text PDF PubMed Google Scholar)CBPdp300 and CBP have high sequence homology and are often interchangeably involved in gene activation.AcetyltransferaseLeads to histone acetylation13–73 (TAD)HG(196Wong C.K. Wade-Vallance A.K. Luciani D.S. Brindle P.K. Lynn F.C. Gibson W.T. The p300 and CBP transcriptional coactivators are required for beta-cell and alpha-cell proliferation.Diabetes. 2018; 67: 412-422Crossref PubMed Scopus (0) Google Scholar)E47aE47 (aka E2A) and β2 (aka NeuroD1) form a heterodimer (often called E47/β2) to bind E-box elements; E47/β2 also interacts with p300.bHLH TFbinds E-box motifsaE47 (aka E2A) and β2 (aka NeuroD1) form a heterodimer (often called E47/β2) to bind E-box elements; E47/β2 also interacts with p300. & Pdx1 via bHLH domain138–213 (HD)HG(95Ohneda K. Mirmira R.G. Wang J. Johnson J.D. German M.S. The homeodomain of PDX-1 mediates multiple protein-protein interactions in the formation of a transcriptional activation complex on the insulin promoter.Mol. Cell. Biol. 2000; 20: 900-911Crossref PubMed Scopus (168) Google Scholar, 195Glick E. Leshkowitz D. Walker M.D. Transcription factor BETA2 acts cooperatively with E2A and PDX1 to activate the insulin gene promoter.J. Biol. Chem. 2000; 275: 2199-2204Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar)HDAC-1/-2DeacetylaseDeacetylates H4 to induce chromatin compaction (part of NurD complex)80–283 (post-TAD)LG(31Stanojevic V. Habener J.F. Thomas M.K. Pancreas duodenum homeobox-1 transcriptional activation requires interactions with p300.Endocrinology. 2004; 145: 2918-2928Crossref PubMed Scopus (0) Google Scholar, 75McKenna B. Guo M. Reynolds A. Hara M. Stein R. Dynamic recruitment of functionally distinct Swi/Snf chromatin remodeling complexes modulates Pdx1 activity in islet beta cells.Cell Rep. 2015; 10: 2032-2042Abstract Full Text Full Text PDF PubMed Google Scholar, 112Mosley A.L. Ozcan S. The pancreatic duodenal homeobox-1 protein (Pdx-1) interacts with histone deacetylases Hdac-1 and Hdac-2 on low levels of glucose.J. Biol. Chem. 2004; 279: 54241-54247Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar)HMGA1AT-hook TFEnhances INS activation by Pdx1138–213 (HD)HGcThe study did not investigate the glucose conditions that give rise to this interaction, but glucose conditions were inferred from context.(95Ohneda K. Mirmira R.G. Wang J. Johnson J.D. German M.S. The homeodomain of PDX-1 mediates multiple protein-protein interactions in the formation of a transcriptional activation complex on the insulin promoter.Mol. Cell. Biol. 2000; 20: 900-911Crossref PubMed Scopus (168) Google Scholar)Importin β1ImportinFacilitates Pdx1 nuclear import146–205 (HD)HG(66Guillemain G. da Silva Xavier G. Rafiq I. Leturque A. Rutter G.A. Importin B1 mediates the glucose-stimulated nuclear import of pancreatic and duodenal homeobox-1 in pancreatic islet beta-cells (MIN6).Biochem. J. 2004; 378: 219-227Crossref PubMed Google Scholar)JMJD3DemethylaseRemoves repressive H3K27Me3NSHG(83Wang W. Shi Q. Guo T. Yang Z. Jia Z. Chen P. et al.PDX1 and ISL1 differentially coordinate with epigenetic modifications to regulate insulin gene expression in varied glucose concentrations.Mol. Cell. Endocrinol. 2016; 428: 38-48Crossref PubMed Scopus (19) Google Scholar)MafAbZIP TFBinds C1 elements & augments INS transcriptionNSHG(99Zhao L. Guo M. Matsuoka T.A. Hagman D.K. Parazzoli S.D. Poitout V. et al.The islet beta cell-enriched MafA activator is a key regulator of insulin gene transcription.J. Biol. Chem. 2005; 280: 11887-11894Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar)p300aE47 (aka E2A) and β2 (aka NeuroD1) form a heterodimer (often called E47/β2) to bind E-box elements; E47/β2 also interacts with p300.,dp300 and CBP have high sequence homology and are often interchangeably involved in gene activation.AcetyltransferaseLeads to H4 hyperacetylation13–22, 32–38, 60–73 (TAD)HG(87Qiu Y. Guo M. Huang S. Stein R. Insulin gene transcription is mediated by interactions between the p300 coactivator and PDX-1, BETA2, and E47.Mol. Cell. Biol. 2002; 22: 412-420Crossref PubMed Scopus (155) Google Scholar, 88Mosley A.L. Corbett J.A. Ozcan S. Glucose regulation of insulin gene expression requires the recruitment of p300 by the beta-cell-specific transcription factor Pdx-1.Mol. Endocrinol. 2004; 18: 2279-2290Crossref PubMed Scopus (99) Google Scholar)RBtumor suppressorstabilizes & prevents Pdx1 ubiquitination153–167 (in HD)HG(70Kim Y.C. Kim S.Y. Mellado-Gil J.M. Yadav H. Neidermyer W. Kamaraju A.K. et al.RB regulates pancreas development by stabilizing Pdx1.EMBO J. 2011; 30: 1563-1576Crossref PubMed Scopus (24) Google Scholar)Set7/9MethyltransferaseActivates INSs via H3 & Pdx1 methylation1–205 (N-term & HD)HG(39Deering T.G. Ogihara T. Trace A.P. Maier B. Mirmira R.G. Methyltransferase Set7/9 maintains transcription and euchromatin structure at islet-enriched genes.Diabetes. 2009; 58: 185-193Crossref PubMed Scopus (95) Google Scholar, 82Maganti A.V. Maier B. Tersey S.A. Sampley M.L. Mosley A.L. Ozcan S. et al.Transcriptional activity of the islet beta cell factor Pdx1 is augmented by lysine methylation catalyzed by the methyltransferase Set7/9.J. Biol. Chem. 2015; 290: 9812-9822Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar)Sox6HMG TFRepresses Pdx1-driven GSIS1–144 (N-term)LGcThe study did not investigate the glucose conditions that give rise to this interaction, but glucose conditions were inferred from context.(115Iguchi H. Ikeda Y. Okamura M. Tanaka T. Urashima Y. Ohguchi H. et al.SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice.J. Biol. Chem. 2005; 280: 37669-37680Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar)SPOPUbiquitin ligase adapterMediates proteasomal degradation224–236 & 265–275 (C-term)LG(34Liu A. Desai B.M. Stoffers D.A. Identification of PCIF1, a POZ domain protein that inhibits PDX-1 (MODY4) transcriptional activity.Mol. Cell. Biol. 2004; 24: 4372-4383Crossref PubMed Scopus (50) Google Scholar, 118Claiborn K.C. Sachdeva M.M. Cannon C.E. Groff D.N. Singer J.D. Stoffers D.A. Pcif1 modulates Pdx1 protein stability and pancreatic beta cell function and survival in mice.J. Clin. Invest. 2010; 120: 3713-3721Crossref PubMed Scopus (58) Google Scholar)bHLH, basic helix-loop helix DNA-binding domain; bZIP, basic leucine zipper domain; GSIS, glucose-stimulated insulin secretion; HG, high glucose; LG, low glucose; NS, not specified; TALE, transcription activator-like effector; TF, transcription factor.a E47 (aka E2A) and β2 (aka NeuroD1) form a heterodimer (often called E47/β2) to bind E-box elements; E47/β2 also interacts with p300.b Brg1 and Brm incorporation into Swi/Snf is mutually exclusive.c The study did not investigate the glucose conditions that give rise to this interaction, but glucose conditions were inferred from context.d p300 and CBP have high sequence homology and are often interchangeably involved in gene activation.e Bridge-1 was cloned from the INS-1 (rat insulinoma) cell line; PSMD9 is the human homolog. Open table in a new tab bHLH, basic helix-loop helix DNA-binding domain; bZIP, basic leucine zipper domain; GSIS, glucose-stimulated insuli" @default.
• W4306857344 created "2022-10-20" @default.
• W4306857344 creator A5039142010 @default.
• W4306857344 creator A5047930774 @default.
• W4306857344 date "2022-12-01" @default.
• W4306857344 modified "2023-09-29" @default.
• W4306857344 title "Biophysical insights into glucose-dependent transcriptional regulation by PDX1" @default.
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