POU Homeodomain Protein Oct-1 Functions as a Sensor for Cyclic AMP

Cyclic AMP is a fundamentally important second messenger for numerous peptide hormones and neurotransmitters that control gene expression, cell proliferation, and metabolic homeostasis. Here we show that cAMP works with the POU homeodomain protein Oct-1 to regulate gene expression in pancreatic and intestinal endocrine cells. This ubiquitously expressed transcription factor is known as a stress sensor. We found that it also functions as a repressor of Cdx-2, a proglucagon gene activator. Through a mechanism that involves the activation of exchange protein activated by cyclic AMP, elevation of cAMP leads to enhanced phosphorylation and nuclear exclusion of Oct-1 and reduced interactions between Oct-1 or nuclear co-repressors and the Cdx-2 gene promoter, detected by chromatin immunoprecipitation. In rat primary pancreatic islet cells, cAMP elevation also reduces nuclear Oct-1 content, which causes increased proglucagon and proinsulin mRNA expression. Our study therefore identifies a novel mechanism by which cAMP regulates hormone-gene expression and suggests that ubiquitously expressed Oct-1 may play a role in metabolic homeostasis by functioning as a sensor for cAMP. Cyclic AMP is a fundamentally important second messenger for numerous peptide hormones and neurotransmitters that control gene expression, cell proliferation, and metabolic homeostasis. Here we show that cAMP works with the POU homeodomain protein Oct-1 to regulate gene expression in pancreatic and intestinal endocrine cells. This ubiquitously expressed transcription factor is known as a stress sensor. We found that it also functions as a repressor of Cdx-2, a proglucagon gene activator. Through a mechanism that involves the activation of exchange protein activated by cyclic AMP, elevation of cAMP leads to enhanced phosphorylation and nuclear exclusion of Oct-1 and reduced interactions between Oct-1 or nuclear co-repressors and the Cdx-2 gene promoter, detected by chromatin immunoprecipitation. In rat primary pancreatic islet cells, cAMP elevation also reduces nuclear Oct-1 content, which causes increased proglucagon and proinsulin mRNA expression. Our study therefore identifies a novel mechanism by which cAMP regulates hormone-gene expression and suggests that ubiquitously expressed Oct-1 may play a role in metabolic homeostasis by functioning as a sensor for cAMP. Many peptide hormones and neurotransmitters use the second messengers, such as cyclic AMP (cAMP), to exert their biological functions, including regulation of gene expression and metabolic homeostasis (1Montminy M. Annu. Rev. Biochem. 1997; 66: 807-822Crossref PubMed Scopus (854) Google Scholar, 2Zhang X. Odom D.T. Koo S.H. Conkright M.D. Canettieri G. Best J. Chen H. Jenner R. Herbolsheimer E. Jacobsen E. Kadam S. Ecker J.R. Emerson B. Hogenesch J.B. Unterman T. Young R.A. Montminy M. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 4459-4464Crossref PubMed Scopus (757) Google Scholar, 3Richards J.S. Mol. Endocrinol. 2001; 15: 209-218Crossref PubMed Scopus (340) Google Scholar, 4Bos J.L. Nat. Rev. Mol. Cell Biol. 2003; 4: 733-738Crossref PubMed Scopus (412) Google Scholar, 5Bos J.L. Trends Biochem. Sci. 2006; 31: 680-686Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar, 6Holz G.G. Diabetes. 2004; 53: 5-13Crossref PubMed Scopus (292) Google Scholar, 7Bos J.L. de Bruyn K. Enserink J. Kuiperij B. Rangarajan S. Rehmann H. Riedl J. de Rooij J. van Mansfeld F. Zwartkruis F. Biochem. Soc. Trans. 2003; 31: 83-86Crossref PubMed Google Scholar). Extensive studies have shown that in addition to the activation of protein kinase A (PKA), 5The abbreviations used are: PKAprotein kinase AEpacexchange protein directly activated by cAMPOCToctamer-binding siteOct-1octamer transcription factor-1siRNAsmall interfering RNARTreverse transcriptionIBMX3-isobutyl-1-methylxanthineChIPchromatin immunoprecipitationERKextracellular signal-regulated kinaseMEKmitogen-activated protein kinase/ERK kinasepolpolymeraseoxLDLoxidized low density lipoproteinEGFPenhanced green fluorescent proteinCREBcAMP-response element-binding proteinCYPcytochrome P450. 5The abbreviations used are: PKAprotein kinase AEpacexchange protein directly activated by cAMPOCToctamer-binding siteOct-1octamer transcription factor-1siRNAsmall interfering RNARTreverse transcriptionIBMX3-isobutyl-1-methylxanthineChIPchromatin immunoprecipitationERKextracellular signal-regulated kinaseMEKmitogen-activated protein kinase/ERK kinasepolpolymeraseoxLDLoxidized low density lipoproteinEGFPenhanced green fluorescent proteinCREBcAMP-response element-binding proteinCYPcytochrome P450. cAMP is able to trigger intracellular signaling events via other mechanisms, including Epac (the activation of exchangeprotein directly activated by cAMP) (8Kawasaki H. Springett G.M. Mochizuki N. Toki S. Nakaya M. Matsuda M. Housman D.E. Graybiel A.M. Science. 1998; 282: 2275-2279Crossref PubMed Scopus (1165) Google Scholar, 9de Rooij J. Zwartkruis F.J. Verheijen M.H. Cool R.H. Nijman S.M. Wittinghofer A. Bos J.L. Nature. 1998; 396: 474-477Crossref PubMed Scopus (1604) Google Scholar, 10Holz G.G. Kang G. Harbeck M. Roe M.W. Chepurny O.G. J. Physiol. 2006; 577: 5-15Crossref PubMed Scopus (228) Google Scholar, 11Rehmann H. Arias-Palomo E. Hadders M.A. Schwede F. Llorca O. Bos J.L. Nature. 2008; 455: 124-127Crossref PubMed Scopus (145) Google Scholar, 12Holz G.G. Chepurny O.G. Schwede F. Cell. Signal. 2008; 20: 10-20Crossref PubMed Scopus (140) Google Scholar, 13Lyle K.S. Raaijmakers J.H. Bruinsma W. Bos J.L. de Rooij J. Cell. Signal. 2008; 20: 1104-1116Crossref PubMed Scopus (45) Google Scholar). As non-kinase effectors of cAMP, Epac molecules are evidently involved in regulating gene expression, cell adhesion, and pancreatic peptide hormone secretion (4Bos J.L. Nat. Rev. Mol. Cell Biol. 2003; 4: 733-738Crossref PubMed Scopus (412) Google Scholar, 10Holz G.G. Kang G. Harbeck M. Roe M.W. Chepurny O.G. J. Physiol. 2006; 577: 5-15Crossref PubMed Scopus (228) Google Scholar, 12Holz G.G. Chepurny O.G. Schwede F. Cell. Signal. 2008; 20: 10-20Crossref PubMed Scopus (140) Google Scholar, 14Lotfi S. Li Z. Sun J. Zuo Y. Lam P.P. Kang Y. Rahimi M. Islam D. Wang P. Gaisano H.Y. Jin T. Endocrinology. 2006; 147: 3727-3736Crossref PubMed Scopus (39) Google Scholar).In pancreatic islet and intestinal endocrine L cells, cAMP elevation is associated with increased expression of proglucagon (gcg) or proinsulin genes (15Nielsen D.A. Welsh M. Casadaban M.J. Steiner D.F. J. Biol. Chem. 1985; 260: 13585-13589Abstract Full Text PDF PubMed Google Scholar, 16Drucker D.J. Philippe J. Mojsov S. Chick W.L. Habener J.F. Proc. Natl. Acad. Sci. U.S.A. 1987; 84: 3434-3438Crossref PubMed Scopus (689) Google Scholar). Expression of these two hormone-encoding genes is also controlled by transcriptional activators, including certain homeodomain proteins such as the caudal homeodomain protein Cdx-2 (17German M.S. Wang J. Chadwick R.B. Rutter W.J. Genes Dev. 1992; 6: 2165-2176Crossref PubMed Scopus (359) Google Scholar, 18Jin T. Drucker D.J. Mol. Cell. Biol. 1996; 16: 19-28Crossref PubMed Scopus (114) Google Scholar, 19Zhao Y. Liu T. Zhang N. Yi F. Wang Q. Fantus I.G. Jin T. J. Endocrinol. 2005; 186: 179-192Crossref PubMed Scopus (5) Google Scholar, 20Laser B. Meda P. Constant I. Philippe J. J. Biol. Chem. 1996; 271: 28984-28994Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 21Ritz-Laser B. Estreicher A. Klages N. Saule S. Philippe J. J. Biol. Chem. 1999; 274: 4124-4132Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 22Hussain M.A. Habener J.F. J. Biol. Chem. 1999; 274: 28950-28957Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). We have demonstrated previously that in both PKA-active and PKA-deficient pancreatic and intestinal proglucagon-producing endocrine cell lines, cAMP elevation leads to increased Cdx-2 expression (23Chen L. Wang P. Andrade C.F. Zhao I.Y. Dubé P.E. Brubaker P.L. Liu M. Jin T. FEBS J. 2005; 272: 2746-2759Crossref PubMed Scopus (28) Google Scholar). Furthermore, Cdx-2 expression in a PKA-deficient pancreatic islet InR1-G9 cell line can be activated by an Epac pathway-specific cAMP analogue 8-pMeOPT-2′-O-Me-cAMP (23Chen L. Wang P. Andrade C.F. Zhao I.Y. Dubé P.E. Brubaker P.L. Liu M. Jin T. FEBS J. 2005; 272: 2746-2759Crossref PubMed Scopus (28) Google Scholar). More recently, we have observed expression of Epac2 in pancreatic and intestinal proglucagon-producing cells and demonstrated that Epac signaling serves as the mediator of cAMP in regulating the expression of gcg (14Lotfi S. Li Z. Sun J. Zuo Y. Lam P.P. Kang Y. Rahimi M. Islam D. Wang P. Gaisano H.Y. Jin T. Endocrinology. 2006; 147: 3727-3736Crossref PubMed Scopus (39) Google Scholar).In this study, we further explored mechanistically how cAMP-Epac signaling activates Cdx-2 expression in pancreatic and intestinal endocrine cells. Our observations suggest the existence of a novel mechanism by which cAMP regulates pancreatic and intestinal hormone-gene expression. It is likely that this regulation involves nuclear-cytoplasmic shuttling of the POU homeodomain protein Oct-1.Oct-1 is a ubiquitously expressed transcriptional regulator with a POU-type DNA binding domain (24Herr W. Sturm R.A. Clerc R.G. Corcoran L.M. Baltimore D. Sharp P.A. Ingraham H.A. Rosenfeld M.G. Finney M. Ruvkun G. et al.Genes Dev. 1988; 2: 1513-1516Crossref PubMed Scopus (599) Google Scholar, 25Wysocka J. Herr W. Trends Biochem. Sci. 2003; 28: 294-304Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar). It exerts multiple biological functions via up- or down-regulating the expression of many target genes in different cell lineages, including endocrine and neuroendocrine cells (13Lyle K.S. Raaijmakers J.H. Bruinsma W. Bos J.L. de Rooij J. Cell. Signal. 2008; 20: 1104-1116Crossref PubMed Scopus (45) Google Scholar, 25Wysocka J. Herr W. Trends Biochem. Sci. 2003; 28: 294-304Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, 26Chandran U.R. Attardi B. Friedman R. Zheng Z. Roberts J.L. DeFranco D.B. J. Biol. Chem. 1996; 271: 20412-20420Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 27Chandran U.R. Warren B.S. Baumann C.T. Hager G.L. DeFranco D.B. J. Biol. Chem. 1999; 274: 2372-2378Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 28Tang Q. Mazur M. Mellon P.L. Mol. Endocrinol. 2005; 19: 2769-2779Crossref PubMed Scopus (20) Google Scholar, 29Belsham D.D. Mellon P.L. Mol. Endocrinol. 2000; 14: 212-228PubMed Google Scholar, 30Vazquez-Martinez R. Leclerc G.M. Wierman M.E. Boockfor F.R. Mol. Endocrinol. 2002; 16: 2093-2100Crossref PubMed Scopus (20) Google Scholar, 31Cheng C.K. Yeung C.M. Chow B.K. Leung P.C. Mol. Endocrinol. 2002; 16: 1552-1564Crossref PubMed Scopus (44) Google Scholar, 32Kiyota T. Kato A. Altmann C.R. Kato Y. Dev. Biol. 2008; 315: 579-592Crossref PubMed Scopus (34) Google Scholar, 33Thum T. Borlak J. J. Biol. Chem. 2008; 283: 19456-19464Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). In this study, we found that in proglucagon-expressing endocrine cells, activation of Epac signaling in response to cAMP elevation reduced nuclear Oct-1 content, an event associated with enhanced Cdx-2 and gcg expression. In rat primary pancreatic islet cells, reduction in nuclear levels of Oct-1 in response to cAMP elevation was shown to be associated with enhanced gcg and proinsulin I mRNA expression. Many peptide hormones and neurotransmitters use the second messengers, such as cyclic AMP (cAMP), to exert their biological functions, including regulation of gene expression and metabolic homeostasis (1Montminy M. Annu. Rev. Biochem. 1997; 66: 807-822Crossref PubMed Scopus (854) Google Scholar, 2Zhang X. Odom D.T. Koo S.H. Conkright M.D. Canettieri G. Best J. Chen H. Jenner R. Herbolsheimer E. Jacobsen E. Kadam S. Ecker J.R. Emerson B. Hogenesch J.B. Unterman T. Young R.A. Montminy M. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 4459-4464Crossref PubMed Scopus (757) Google Scholar, 3Richards J.S. Mol. Endocrinol. 2001; 15: 209-218Crossref PubMed Scopus (340) Google Scholar, 4Bos J.L. Nat. Rev. Mol. Cell Biol. 2003; 4: 733-738Crossref PubMed Scopus (412) Google Scholar, 5Bos J.L. Trends Biochem. Sci. 2006; 31: 680-686Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar, 6Holz G.G. Diabetes. 2004; 53: 5-13Crossref PubMed Scopus (292) Google Scholar, 7Bos J.L. de Bruyn K. Enserink J. Kuiperij B. Rangarajan S. Rehmann H. Riedl J. de Rooij J. van Mansfeld F. Zwartkruis F. Biochem. Soc. Trans. 2003; 31: 83-86Crossref PubMed Google Scholar). Extensive studies have shown that in addition to the activation of protein kinase A (PKA), 5The abbreviations used are: PKAprotein kinase AEpacexchange protein directly activated by cAMPOCToctamer-binding siteOct-1octamer transcription factor-1siRNAsmall interfering RNARTreverse transcriptionIBMX3-isobutyl-1-methylxanthineChIPchromatin immunoprecipitationERKextracellular signal-regulated kinaseMEKmitogen-activated protein kinase/ERK kinasepolpolymeraseoxLDLoxidized low density lipoproteinEGFPenhanced green fluorescent proteinCREBcAMP-response element-binding proteinCYPcytochrome P450. 5The abbreviations used are: PKAprotein kinase AEpacexchange protein directly activated by cAMPOCToctamer-binding siteOct-1octamer transcription factor-1siRNAsmall interfering RNARTreverse transcriptionIBMX3-isobutyl-1-methylxanthineChIPchromatin immunoprecipitationERKextracellular signal-regulated kinaseMEKmitogen-activated protein kinase/ERK kinasepolpolymeraseoxLDLoxidized low density lipoproteinEGFPenhanced green fluorescent proteinCREBcAMP-response element-binding proteinCYPcytochrome P450. cAMP is able to trigger intracellular signaling events via other mechanisms, including Epac (the activation of exchangeprotein directly activated by cAMP) (8Kawasaki H. Springett G.M. Mochizuki N. Toki S. Nakaya M. Matsuda M. Housman D.E. Graybiel A.M. Science. 1998; 282: 2275-2279Crossref PubMed Scopus (1165) Google Scholar, 9de Rooij J. Zwartkruis F.J. Verheijen M.H. Cool R.H. Nijman S.M. Wittinghofer A. Bos J.L. Nature. 1998; 396: 474-477Crossref PubMed Scopus (1604) Google Scholar, 10Holz G.G. Kang G. Harbeck M. Roe M.W. Chepurny O.G. J. Physiol. 2006; 577: 5-15Crossref PubMed Scopus (228) Google Scholar, 11Rehmann H. Arias-Palomo E. Hadders M.A. Schwede F. Llorca O. Bos J.L. Nature. 2008; 455: 124-127Crossref PubMed Scopus (145) Google Scholar, 12Holz G.G. Chepurny O.G. Schwede F. Cell. Signal. 2008; 20: 10-20Crossref PubMed Scopus (140) Google Scholar, 13Lyle K.S. Raaijmakers J.H. Bruinsma W. Bos J.L. de Rooij J. Cell. Signal. 2008; 20: 1104-1116Crossref PubMed Scopus (45) Google Scholar). As non-kinase effectors of cAMP, Epac molecules are evidently involved in regulating gene expression, cell adhesion, and pancreatic peptide hormone secretion (4Bos J.L. Nat. Rev. Mol. Cell Biol. 2003; 4: 733-738Crossref PubMed Scopus (412) Google Scholar, 10Holz G.G. Kang G. Harbeck M. Roe M.W. Chepurny O.G. J. Physiol. 2006; 577: 5-15Crossref PubMed Scopus (228) Google Scholar, 12Holz G.G. Chepurny O.G. Schwede F. Cell. Signal. 2008; 20: 10-20Crossref PubMed Scopus (140) Google Scholar, 14Lotfi S. Li Z. Sun J. Zuo Y. Lam P.P. Kang Y. Rahimi M. Islam D. Wang P. Gaisano H.Y. Jin T. Endocrinology. 2006; 147: 3727-3736Crossref PubMed Scopus (39) Google Scholar). protein kinase A exchange protein directly activated by cAMP octamer-binding site octamer transcription factor-1 small interfering RNA reverse transcription 3-isobutyl-1-methylxanthine chromatin immunoprecipitation extracellular signal-regulated kinase mitogen-activated protein kinase/ERK kinase polymerase oxidized low density lipoprotein enhanced green fluorescent protein cAMP-response element-binding protein cytochrome P450. protein kinase A exchange protein directly activated by cAMP octamer-binding site octamer transcription factor-1 small interfering RNA reverse transcription 3-isobutyl-1-methylxanthine chromatin immunoprecipitation extracellular signal-regulated kinase mitogen-activated protein kinase/ERK kinase polymerase oxidized low density lipoprotein enhanced green fluorescent protein cAMP-response element-binding protein cytochrome P450. In pancreatic islet and intestinal endocrine L cells, cAMP elevation is associated with increased expression of proglucagon (gcg) or proinsulin genes (15Nielsen D.A. Welsh M. Casadaban M.J. Steiner D.F. J. Biol. Chem. 1985; 260: 13585-13589Abstract Full Text PDF PubMed Google Scholar, 16Drucker D.J. Philippe J. Mojsov S. Chick W.L. Habener J.F. Proc. Natl. Acad. Sci. U.S.A. 1987; 84: 3434-3438Crossref PubMed Scopus (689) Google Scholar). Expression of these two hormone-encoding genes is also controlled by transcriptional activators, including certain homeodomain proteins such as the caudal homeodomain protein Cdx-2 (17German M.S. Wang J. Chadwick R.B. Rutter W.J. Genes Dev. 1992; 6: 2165-2176Crossref PubMed Scopus (359) Google Scholar, 18Jin T. Drucker D.J. Mol. Cell. Biol. 1996; 16: 19-28Crossref PubMed Scopus (114) Google Scholar, 19Zhao Y. Liu T. Zhang N. Yi F. Wang Q. Fantus I.G. Jin T. J. Endocrinol. 2005; 186: 179-192Crossref PubMed Scopus (5) Google Scholar, 20Laser B. Meda P. Constant I. Philippe J. J. Biol. Chem. 1996; 271: 28984-28994Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 21Ritz-Laser B. Estreicher A. Klages N. Saule S. Philippe J. J. Biol. Chem. 1999; 274: 4124-4132Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 22Hussain M.A. Habener J.F. J. Biol. Chem. 1999; 274: 28950-28957Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). We have demonstrated previously that in both PKA-active and PKA-deficient pancreatic and intestinal proglucagon-producing endocrine cell lines, cAMP elevation leads to increased Cdx-2 expression (23Chen L. Wang P. Andrade C.F. Zhao I.Y. Dubé P.E. Brubaker P.L. Liu M. Jin T. FEBS J. 2005; 272: 2746-2759Crossref PubMed Scopus (28) Google Scholar). Furthermore, Cdx-2 expression in a PKA-deficient pancreatic islet InR1-G9 cell line can be activated by an Epac pathway-specific cAMP analogue 8-pMeOPT-2′-O-Me-cAMP (23Chen L. Wang P. Andrade C.F. Zhao I.Y. Dubé P.E. Brubaker P.L. Liu M. Jin T. FEBS J. 2005; 272: 2746-2759Crossref PubMed Scopus (28) Google Scholar). More recently, we have observed expression of Epac2 in pancreatic and intestinal proglucagon-producing cells and demonstrated that Epac signaling serves as the mediator of cAMP in regulating the expression of gcg (14Lotfi S. Li Z. Sun J. Zuo Y. Lam P.P. Kang Y. Rahimi M. Islam D. Wang P. Gaisano H.Y. Jin T. Endocrinology. 2006; 147: 3727-3736Crossref PubMed Scopus (39) Google Scholar). In this study, we further explored mechanistically how cAMP-Epac signaling activates Cdx-2 expression in pancreatic and intestinal endocrine cells. Our observations suggest the existence of a novel mechanism by which cAMP regulates pancreatic and intestinal hormone-gene expression. It is likely that this regulation involves nuclear-cytoplasmic shuttling of the POU homeodomain protein Oct-1. Oct-1 is a ubiquitously expressed transcriptional regulator with a POU-type DNA binding domain (24Herr W. Sturm R.A. Clerc R.G. Corcoran L.M. Baltimore D. Sharp P.A. Ingraham H.A. Rosenfeld M.G. Finney M. Ruvkun G. et al.Genes Dev. 1988; 2: 1513-1516Crossref PubMed Scopus (599) Google Scholar, 25Wysocka J. Herr W. Trends Biochem. Sci. 2003; 28: 294-304Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar). It exerts multiple biological functions via up- or down-regulating the expression of many target genes in different cell lineages, including endocrine and neuroendocrine cells (13Lyle K.S. Raaijmakers J.H. Bruinsma W. Bos J.L. de Rooij J. Cell. Signal. 2008; 20: 1104-1116Crossref PubMed Scopus (45) Google Scholar, 25Wysocka J. Herr W. Trends Biochem. Sci. 2003; 28: 294-304Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, 26Chandran U.R. Attardi B. Friedman R. Zheng Z. Roberts J.L. DeFranco D.B. J. Biol. Chem. 1996; 271: 20412-20420Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 27Chandran U.R. Warren B.S. Baumann C.T. Hager G.L. DeFranco D.B. J. Biol. Chem. 1999; 274: 2372-2378Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 28Tang Q. Mazur M. Mellon P.L. Mol. Endocrinol. 2005; 19: 2769-2779Crossref PubMed Scopus (20) Google Scholar, 29Belsham D.D. Mellon P.L. Mol. Endocrinol. 2000; 14: 212-228PubMed Google Scholar, 30Vazquez-Martinez R. Leclerc G.M. Wierman M.E. Boockfor F.R. Mol. Endocrinol. 2002; 16: 2093-2100Crossref PubMed Scopus (20) Google Scholar, 31Cheng C.K. Yeung C.M. Chow B.K. Leung P.C. Mol. Endocrinol. 2002; 16: 1552-1564Crossref PubMed Scopus (44) Google Scholar, 32Kiyota T. Kato A. Altmann C.R. Kato Y. Dev. Biol. 2008; 315: 579-592Crossref PubMed Scopus (34) Google Scholar, 33Thum T. Borlak J. J. Biol. Chem. 2008; 283: 19456-19464Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). In this study, we found that in proglucagon-expressing endocrine cells, activation of Epac signaling in response to cAMP elevation reduced nuclear Oct-1 content, an event associated with enhanced Cdx-2 and gcg expression. In rat primary pancreatic islet cells, reduction in nuclear levels of Oct-1 in response to cAMP elevation was shown to be associated with enhanced gcg and proinsulin I mRNA expression. We thank Dr. Winship Herr for the original human Oct-1 expression plasmid; Drs. Donald Branch, Weiyang Lu, Allen Volchuk, and Burton Yang for their valuable comments; and Yanchun Wang for technical assistance. Supplementary Material Download .pdf (.02 MB) Help with pdf files Download .pdf (.02 MB) Help with pdf files

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