Transcriptional Regulation of Cyclin D2 by the PKA Pathway and Inducible cAMP Early Repressor in Granulosa Cells1

Muñiz, Luis C.; Yehia, Ghassan; Mémin, Elisabeth; Ratnakar, Pillarisetty V.A.L.; Molina, Carlos A.

doi:10.1095/biolreprod.105.049486

Cited by 21 publications

(11 citation statements)

References 42 publications

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“…Our findings suggest a differentiated response of ␤-cells to extracellular growth factors with cyclin A2 being responsive to the cAMP-PKA-CREB-CBP pathway, whereas the D-type cyclins possibly respond to growth factor stimuli other than cAMP or PI 3-kinase (36). Previous reports have suggested that cyclins D1 and D2 respond to the cAMP pathway in in vitro cell systems (37)(38)(39). We do not find any evidence for exendin-4 or CREB-CBPmediated elevation in D-type cyclins.…”

Section: Exendin-4 Stimulation Of Cyclin A2mentioning

confidence: 61%

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

et al. 2008

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OBJECTIVE-␤-Cell proliferation is an important mechanism underlying ␤-cell mass adaptation to metabolic demands. We have examined effects, in particular those mediated through intracellular cAMP signaling, of the incretin hormone analog exendin-4 on cell cycle regulation in ␤-cells.RESEARCH DESIGN AND METHODS-Changes in islet protein levels of cyclins and of two critical cell cycle regulators cyclin kinase inhibitor p27 and S-phase kinase-associated protein 2 (Skp2) were assessed in mice treated with exendin-4 and in a mouse model with specific upregulation of nuclear cAMP signaling exhibiting increased ␤-cell proliferation (CBP-S436A mouse). Because cyclin A2 was stimulated by cAMP, we assessed the role of cylcin A2 in cell cycle progression in Min6 and isolated islet ␤-cells.RESULTS-Mice treated with exendin-4 showed increased ␤-cell proliferation, elevated islet protein levels of cyclin A2 with unchanged D-type cyclins, elevated PDX-1 and Skp2 levels, and reduced p27 levels. Exendin-4 stimulated cyclin A2 promoter activity via the cAMP-cAMP response element binding protein pathway. CBP-S436A islets exhibited elevated cyclin A2, reduced p27, and no changes in D-type cyclins, PDX-1, or Skp2. In cultured islets, exendin-4 increased cyclin A2 and Skp2 and reduced p27. Cyclin A2 overexpression in primary islets increased proliferation and reduced p27. In Min6 cells, cyclin A2 knockdown prevented exendin-4 -stimulated proliferation. PDX-1 knockdown reduced exendin-4 -stimulated cAMP synthesis and cyclin A2 transcription.CONCLUSIONS-Cyclin A2 is required for ␤-cell proliferation, exendin-4 stimulates cyclin A2 expression via the cAMP pathway, and exendin-4 stimulation of cAMP requires PDX-1. Diabetes 57:2371-2381, 2008 P ancreatic ␤-cell mass is dynamic and responds to variations in metabolic demand on insulin production. The inability of the endocrine pancreas to adapt to changing insulin demand (inadequate ␤-cell mass) is found both in type 1 and type 2 diabetes. Increasing ␤-cell mass by regeneration may ameliorate or correct both type 1 and 2 diabetes (1). Within the pancreas, ␤-cells regenerate predominantly by ␤-cell replication (2,3). In this context, insight into the mechanisms underlying ␤-cell proliferation and cell cycle regulation, may provide potential targets for therapy in situations of inadequate ␤-cell mass.The incretin hormone glucagon-like peptide-1 (GLP-1) and its long-acting peptide analog exendin-4 stimulate ␤-cell proliferation in vitro and in vivo (4), leading to increased ␤-cell mass in rodents and amelioration of glucose metabolism in diabetic animal models and human diabetic subjects (4). Downstream effectors of the GLP-1 signaling to the cell nucleus include 1) the epidermal growth factor receptor-phosphoinositol 3-kinase (PI 3-kinase)-protein kinase B (PKB/Akt)-forkhead box transcription factor O1 (FoxO1) pathway (5) and 2) the cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB) pathway (4). Activation of the PI 3-kinase pathway results in phosphorylation and nuclear...

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Section: Exendin-4 Stimulation Of Cyclin A2mentioning

confidence: 61%

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

et al. 2008

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Section: Discussionmentioning

confidence: 79%

“…We (above) and others (24,29) have found that cAMP signaling has a potent effect on CCND2 transcription, which is mediated by a conserved CRE site located immediately 5′ to the transcriptional origin (29). CREM repressors regulate CCND2 by binding this CRE (24). Repressor isoforms of CREM share the DNA binding and dimerization domains of CREM activators but lack kinase and trans-activation domains and therefore act as potent dominant negative transcription inhibitors (30)(31)(32).…”

Section: Discussionmentioning

confidence: 90%

“…Upregulation of CREM repressor Figure 8B) using primers that target the isoforms (ICER1 and CREM1α) that gene-expression analysis had revealed were expressed at increased levels; 3-to 6-fold induction of these CREM transcripts by PCR in H929 and U266 MM cells was detected, consistent with the results of gene-expression profiling. Expression of cyclin D1 in MM has previously been shown to be critically dependent upon a CRE site in the CCND1 promoter (26); CCND2 is similarly responsive to cAMP via a CRE site in its own promoter and responds to CREM repressor control (24). In KMS11 myeloma cells, plasmid-mediated expression of the induced CREM repressor cDNA caused suppression of CCND2 promoter activity, measured by LUC reporter (Figure 8C), supporting a role for kinetin riboside-induced CREM repressor expression in the modulation of CCND2 promoter activity by kinetin riboside.…”

Section: Figurementioning

confidence: 99%

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Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity

Tiedemann¹,

Mao²,

Shi³

et al. 2008

J. Clin. Invest.

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Knockout and transgenic studies in mice demonstrate that normal somatic tissues redundantly express 3 cyclin D proteins, whereas tumor cells seem dependent on a single overexpressed cyclin D. Thus, selective suppression of the individual cyclin D deregulated in a tumor represents a biologically valid approach to targeted cancer therapy. In multiple myeloma, overexpression of 1 of the cyclin D proteins is a ubiquitous feature, unifying at least 7 different initiating genetic events. We demonstrate here that RNAi of genes encoding cyclin D1 and cyclin D2 (CCND1 and CCND2, respectively) inhibits proliferation and is progressively cytotoxic in human myeloma cells. By screening a chemical library using a cell-based assay for inhibition of CCND2 trans-activation, we identified the plant cytokinin kinetin riboside as an inhibitor of CCND2 trans-activation. Kinetin riboside induced marked suppression of CCND2 transcription and rapidly suppressed cyclin D1 and D2 protein expression in primary myeloma cells and tumor lines, causing cell-cycle arrest, tumor cell-selective apoptosis, and inhibition of myeloma growth in xenografted mice. Mechanistically, kinetin riboside upregulated expression of transcription repressor isoforms of cAMP-response element modulator (CREM) and blocked both trans-activation of CCND2 by various myeloma oncogenes and cis-activation of translocated CCND1, suggesting induction of an overriding repressor activity that blocks multiple oncogenic pathways targeting cyclin D genes. These data support targeted repression of cyclin D genes as a therapeutic strategy for human malignancies. IntroductionMultiple myeloma (MM) is a postgerminal center B cell malignancy characterized by clonal plasma cell expansion. The disease manifests clinically with anemia, monoclonal immunoglobulin, renal insufficiency, and lytic bone lesions and currently affects 63,000 people in the United States alone (1); moreover, as it is currently incurable, MM causes a disproportionate 2% of all cancer deaths.Although myeloma tumors present with complex karyotypes and an assortment of structural and numerical chromosomal abnormalities, these tumors are unified in their ubiquitous targeting of cyclin D genes for overexpression. Of MM tumors, 54% overexpress cyclin D1 (CCND1), 48% overexpress cyclin D2 (CCND2), 3% overexpress cyclin D3 (CCND3), and 8% overexpress both CCND1 and CCND2 (2). Deregulated expression of single CCND genes in MM occurs as the result of selective cyclin D gene trans-activation by deregulated transcription factors or from translocation of a single

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“…The question of whether loss of G s ␣/cAMP signaling directly leads to cyclin D2 deficiency in ␤ cells requires further study, although recent studies in both lymphocytes and ovarian granulosa cells demonstrated that cAMP induces the Ccnd2 gene promoter via binding of PKA-phosphorylated CREB to a CREB binding site (31,32). Cyclin D2 and its associated cyclin-dependent kinase cdk4 have both been shown to be critical regulators of ␤ cell proliferation and ␤ cell mass (3)(4)(5)(6)(7)33).…”

Section: Discussionmentioning

confidence: 99%

β cell-specific deficiency of the stimulatory G protein α-subunit G _s α leads to reduced β cell mass and insulin-deficient diabetes

Xie

Chen

Zhang

et al. 2007

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

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The G protein ␣-subunit Gs␣ is required for hormone-stimulated cAMP generation. In pancreatic ␤ cells, Gs␣ mediates the signaling of glucagon-like peptide 1 and other incretin hormones, which are implicated as important regulators of ␤ cell survival and insulin release. Studies have suggested that G s␣/cAMP mediates these actions by stimulating insulin receptor substrate 2 (IRS2) expression. Mice with ␤ cell-specific Gs␣ deficiency (␤GsKO) were generated by mating G s␣-floxed mice to rat insulin II promoter-cre recombinase mice. ␤GsKO mice had poor survival and postnatal growth with low serum insulin-like growth factor 1 levels. ␤GsKO mice also developed severe hyperglycemia and glucose intolerance with severe hypoinsulinemia and reduced islet insulin content and glucose-stimulated insulin release. ␤GsKO mice had markedly reduced average islet size and ␤ cell mass, which was partially explained by reduced ␤ cell size. In addition, ␤GsKO mice had significantly reduced ␤ cell proliferation and increased ␤ cell apoptosis and markedly reduced expression of the cell cycle protein cyclin D2. The effects on ␤ cell mass and proliferation, but not apoptosis, were present from birth. Unexpectedly expression of Irs2 and the downstream gene Pdx1 were unaffected. These results show that G s␣/cAMP pathways are critical regulators of ␤ cell function and proliferation that can work through IRS2-independent mechanisms.

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Transcriptional Regulation of Cyclin D2 by the PKA Pathway and Inducible cAMP Early Repressor in Granulosa Cells1

Cited by 21 publications

References 42 publications

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity

β cell-specific deficiency of the stimulatory G protein α-subunit G _s α leads to reduced β cell mass and insulin-deficient diabetes

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Transcriptional Regulation of Cyclin D2 by the PKA Pathway and Inducible cAMP Early Repressor in Granulosa Cells1

Cited by 21 publications

References 42 publications

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity

β cell-specific deficiency of the stimulatory G protein α-subunit G s α leads to reduced β cell mass and insulin-deficient diabetes

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β cell-specific deficiency of the stimulatory G protein α-subunit G _s α leads to reduced β cell mass and insulin-deficient diabetes