Overexpression of Inducible Cyclic AMP Early Repressor Inhibits Transactivation of Genes and Cell Proliferation in Pancreatic β Cells

Inada, Akira; Hamamoto, Yoshiyuki; Tsuura, Yoshiyuki; Miyazaki, Jun‐ichi; Toyokuni, Shinya; Ihara, Yu; Nagai, Kiyohisa; Yamada, Yoshio; Bonner-Weir, Susan; Seino, Yutaka

doi:10.1128/mcb.24.7.2831-2841.2004

Cited by 70 publications

(78 citation statements)

References 56 publications

(51 reference statements)

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“…CREB is a transcription factor with critical survival gene targets and loss of CREB function leads to mouse beta cell apoptosis in vitro and in vivo [13,17,18]. In this study, we demonstrate that when CREB-mediated transcription is downregulated by dominant negative mutant forms of CREB (MCREB and KCREB), the apoptotic profile of human islets in the transplantation setting is modified.…”

Section: Discussionmentioning

confidence: 78%

“…Although recent reports [13,17,18] have suggested that CREB plays a role in beta cell survival, no previous study has examined its role in the survival of human islets. The objectives of the present study were to determine the effects CREB downregulation in human islets and to examine the anti-apoptotic actions of the beta cell-specific growth factors in islets exposed to cytokines.…”

Section: Introductionmentioning

confidence: 99%

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Dominant negative mutant forms of the cAMP response element binding protein induce apoptosis and decrease the anti-apoptotic action of growth factors in human islets

Sarkar¹,

Gunter

Bouchard

et al. 2007

Diabetologia

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Aims/hypothesis Transplantation of islets is a viable option for the treatment of diabetes. A significant proportion of islets is lost during isolation, storage and after transplantation as a result of apoptosis. cAMP response element binding protein (CREB) is an important cell survival factor. The aim of the present study was to determine whether preservation of CREB function is needed for survival of human islets. Materials and methods To determine the effects of downregulation of CREB activity on beta cell apoptosis in a transplantation setting, adenoviral vectors were used to express two dominant negative mutant forms of CREB in human islets isolated from cadaveric donors. Markers of apoptosis were determined in these transduced islets under basal conditions and following treatment with growth factor. Results Expression of CREB mutants in human islets resulted in significant (p<0.001) activation of caspase-9, a key regulatory enzyme in the mitochondrial pathway of apoptosis, when compared with islets transduced with adenoviral beta galactosidase. Immunocytochemical analysis showed the activation of caspase-9 to be predominantly in beta cells. Other definitive markers of apoptosis such as parallel activation of caspase-3, accumulation of cleaved poly-(ADP-ribose) polymerase and nuclear condensation were also observed. Furthermore, the anti-apoptotic action of growth factors exendin-4 and betacellulin in human islets exposed to cytokines was partially lost when CREB function was impaired. Conclusions/interpretation Our findings suggest that impairment of CREB-mediated transcription could lead to loss of islets by apoptosis with potential implications in islet transplantation as well as in the mechanism of beta cell loss leading to diabetes.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Dominant negative mutant forms of the cAMP response element binding protein induce apoptosis and decrease the anti-apoptotic action of growth factors in human islets

Sarkar¹,

Gunter

Bouchard

et al. 2007

Diabetologia

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“…Indeed, the notion that CREB coordinates with other transcription factors is supported by recent animal studies in which CREB appeared to elicit the expression of distinct genetic programs in different tissues (9)(10)(11). Thus, depending on cellular context, CREB activity may be targeted to certain genes at the level of promoter occupancy, Ser-133 phosphorylation, or recruitment of the transcriptional apparatus.…”

mentioning

confidence: 59%

“…In keeping with the role of CREB in promoting islet cell proliferation and viability (10,11), exposure of cultured human islets to cAMP stimulated a number of growth factor genes and antiapoptotic factors. By contrast, exposure of primary hepatocytes to cAMP induced genes involved in fasting glucose and lipid metabolism.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues

Zhang

Odom

Koo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

902

867

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Hormones and nutrients often induce genetic programs via signaling pathways that interface with gene-specific activators. Activation of the cAMP pathway, for example, stimulates cellular gene expression by means of the PKA-mediated phosphorylation of cAMP-response element binding protein (CREB) at Ser-133. Here, we use genome-wide approaches to characterize target genes that are regulated by CREB in different cellular contexts. CREB was found to occupy Ϸ4,000 promoter sites in vivo, depending on the presence and methylation state of consensus cAMP response elements near the promoter. The profiles for CREB occupancy were very similar in different human tissues, and exposure to a cAMP agonist stimulated CREB phosphorylation over a majority of these sites. Only a small proportion of CREB target genes was induced by cAMP in any cell type, however, due in part to the preferential recruitment of the coactivator CREB-binding protein to those promoters. These results indicate that CREB phosphorylation alone is not a reliable predictor of target gene activation and that additional CREB regulatory partners are required for recruitment of the transcriptional apparatus to the promoter.cAMP ͉ cAMP-response element binding protein-binding protein ͉ DNA methylation T he concept of a transcription code that dictates gene expression by means of the concerted action of multiple promoter elements has served as a useful paradigm for understanding specificity in gene regulation. The ability of multiple transcription factors to recruit RNA polymerase II to the promoter by means of low affinity interactions with components of the transcriptional machinery has been documented extensively (1).By contrast with this model, other studies suggest that some activators per se are sufficient to mediate transcriptional responses to hormonal signals depending on the occupancy of relevant sites (1). Indeed, genome-wide studies comparing binding patterns of hepatic nuclear factors in the liver and endocrine pancreas indicate that selective occupancy may often explain how different genetic programs are activated in distinct cell types (2).The cAMP-response element binding protein (CREB) family of activators stimulates cellular gene expression after phosphorylation at a conserved serine (Ser-133 in CREB1) in response to cAMP (3). Ser-133 phosphorylation promotes target gene activation in part by means of recruitment of the coactivator paralogs CREB-binding protein (CBP)͞p300 (4). Recruitment of CBP by phospho-CREB (P-CREB) appears sufficient for induction of cellular genes in response to cAMP (5, 6); in vitro transcription studies indicate that P-CREB is capable of promoting assembly of the transcriptional apparatus independent of other regulatory inputs (7).By contrast, some reports suggest that other upstream activators in addition to CREB are required for cellular gene induction by cAMP (8). Indeed, the notion that CREB coordinates with other transcription factors is supported by recent animal studies in which CREB appeared to elicit the expressi...

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“…Taken together, these data suggest that the decrease in bone mass in ICER I mice was largely due to decreased bone formation. Using a similar in vivo strategy, tissue selective promoters have been used to generate transgenic mice with ICER expression targeted to pancreatic β-cells [36] and thymocytes [37]. bZIP factors are grouped into thirteen families based on their dimerization properties [38].…”

Section: Discussionmentioning

confidence: 99%

Osteopenia in transgenic mice with osteoblast-targeted expression of the inducible cAMP early repressor

Chandhoke¹,

Huang²,

Liu³

et al. 2008

Bone

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ICER is a member of the CREM family of basic leucine zipper transcription factors that acts as a dominant negative regulator of gene transcription. Four different isoforms of ICER (I, Iγ, II and IIγ) are transcribed from the P2 promoter of the Crem gene. We previously found that each of the ICER isoforms is induced by parathyroid hormone in osteoblasts. The goal of the present study was to assess the function of ICER in bone by overexpressing ICER in osteoblasts of transgenic mice. ICER I and ICER II cDNAs, each containing an N-terminal FLAG epitope tag, were cloned downstream of a fragment containing 3.6 kb of the rat Col1a1 promoter and most of the rat Col1a1 first intron to produce pOBCol3.6-ICER I and pOBCol3.6-ICER II transgenes, respectively. Multiple lines of mice were generated bearing the ICER I and ICER II transgenes. At 8 weeks of age, ICER I and ICER II transgenic mice had lower body weights and decreased bone mineral density of femurs and vertebrae. Further studies were done with ICER I transgenic mice, which had had greatly reduced trabecular bone volume and a markedly decreased bone formation rate in femurs. Osteoblast differentiation and osteocalcin expression were reduced in ex vivo bone marrow cultures from ICER I transgenic mice. ICER I antagonized the activity of ATF4 at its consensus DNA binding site in the osteocalcin promoter in vitro. Thus, transgenic mice with osteoblast-targeted overexpression of ICER resulted in osteopenia caused primarily by reduced bone formation. We speculate that ICER regulates the activity and/or expression of ATF/CREB factors required for normal bone formation.

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Overexpression of Inducible Cyclic AMP Early Repressor Inhibits Transactivation of Genes and Cell Proliferation in Pancreatic β Cells

Cited by 70 publications

References 56 publications

Dominant negative mutant forms of the cAMP response element binding protein induce apoptosis and decrease the anti-apoptotic action of growth factors in human islets

Dominant negative mutant forms of the cAMP response element binding protein induce apoptosis and decrease the anti-apoptotic action of growth factors in human islets

Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues

Osteopenia in transgenic mice with osteoblast-targeted expression of the inducible cAMP early repressor

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