Exendin-4 induction of cyclin D1 expression in INS-1 β-cells: involvement of cAMP-responsive element

Kim, Do Young; Kang, Jun‐Myung; Yg, Park; Gr, Ryu; Sh, Ko; Jeong, In‐Kyung; Kh, Koh; Dj, Rhie; Sh, Yoon; Sj, Hahn; Ms, Kim; Yh, Jo

doi:10.1677/joe.1.06480

Cited by 59 publications

(44 citation statements)

References 36 publications

(34 reference statements)

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“…Phosphorylation of Rb was also induced as previously reported (ESM Fig. 1a, b) [12]. Rb levels did not change in response to high glucose, supporting its response specifically to exendin-4.…”

Section: Resultssupporting

confidence: 87%

“…Adult pancreatic islet cells are mostly in the quiescent/G 1/0 state but can re-enter cell cycle following appropriate stimuli. For example, the glucagon-like peptide-1 (GLP-1) analogue, exendin-4, stimulates beta cell proliferation [11,12] while preventing alpha cell expansion [13,14]. However, the mechanisms by which GLP-1 mediates these divergent effects in alpha and beta cells are unknown.…”

Section: Introductionmentioning

confidence: 99%

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Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

Cai

Luk

et al. 2014

Diabetologia

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Aims/hypothesis Diabetes mellitus is characterised by beta cell loss and alpha cell expansion. Analogues of glucagonlike peptide-1 (GLP-1) are used therapeutically to antagonise these processes; thus, we hypothesised that the related cell cycle regulators retinoblastoma protein (Rb) and p107 were involved in GLP-1 action. Methods We used small interfering RNA and adenoviruses to manipulate Rb and p107 expression in insulinoma and alpha-TC cell lines. In vivo we examined pancreas-specific Rb knockout, whole-body p107 knockout and Rb/p107 doubleknockout mice.Results Rb, but not p107, was downregulated in response to the GLP-1 analogue, exendin-4, in both alpha and beta cells. Intriguingly, this resulted in opposite outcomes of cell cycle arrest in alpha cells but proliferation in beta cells. Overexpression of Rb in alpha and beta cells abolished or attenuated the effects of exendin-4 supporting the important role of Rb in GLP-1 modulation of cell cycling. Similarly, in vivo, Rb, but not p107, deficiency was required for the beta cell proliferative response to exendin-4. Consistent with this finding, Rb, but not p107, was suppressed in islets from humans with diabetes, suggesting the importance of Rb regulation for the compensatory proliferation that occurs under insulin resistant conditions. Finally, while p107 alone did not have an essential role in islet homeostasis, when combined with Rb deletion, its absence potentiated apoptosis of both alpha and beta cells resulting in glucose intolerance and diminished islet mass with ageing. Conclusions/interpretation We found a central role of Rb in the dual effects of GLP-1 in alpha and beta cells. Our findings highlight unique contributions of individual Rb family members to islet cell proliferation and survival.

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Section: Resultssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

Cai

Luk

et al. 2014

Diabetologia

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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: 56%

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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“…CREM repressor activity is regulated by gene expression rather than by posttranslational modification (32,33). A functional CRE is also present in CCND1 (34)(35)(36) at a location identical to that in CCND2; however, an analogous CRE is not present in CCND3. Together, these observations demonstrate a mechanism by which kinetin riboside can specifically suppress cyclin D2 and D1, but not D3, blocking gene transcription induced by diverse direct or indirect cis-or trans-activating signals (Supplemental Figure 5).…”

Section: Discussionmentioning

confidence: 99%

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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Exendin-4 induction of cyclin D1 expression in INS-1 β-cells: involvement of cAMP-responsive element

Cited by 59 publications

References 36 publications

Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

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

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