The CDK4–pRB–E2F1 pathway controls insulin secretion

Annicotte, Jean-Sébastien; Blanchet, Élodie; Chavey, Carine; Iankova, Irena; Costes, Safia; Assou, Saïd; Teyssier, Jacques; Dalle, Stéphane; Sardet, Claude; Fajas, Lluís

doi:10.1038/ncb1915

Cited by 120 publications

(143 citation statements)

References 29 publications

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“…We also observed increases in Kir6.2 (also known as Kcnj11) expression in p-Rb and p-DKO mice, which is well known for regulation in insulin secretion and has also been implicated in beta cell proliferation, consistent with its regulation by E2F1 (ESM Fig. 3c) [32,33]. These results show intricate regulation of p53 by Rb family proteins and the fine-tuning of intracellular signalling that is potentiated by Rb and p107.…”

Section: Resultssupporting

confidence: 75%

“…Persistently increased apoptosis with a concomitant reduction in proliferation resulted in net loss of beta cell mass in p-DKO mice with ageing, leading to the loss of improved glucose homeostasis observed in young p-DKO mice. Moreover, E2F1 has previously been shown to be involved in early pancreas development [40], insulin secretion [33,41] and proliferation [41][42][43][44]. These data show the importance of the precise regulation of E2F in determining the various biological outcomes of islets.…”

Section: Discussionmentioning

confidence: 65%

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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: 75%

Section: Discussionmentioning

confidence: 65%

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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“…Also, they demonstrated that the CDK4-pRB-E2F1 pathway could be regulated by insulin signaling in mouse pancreatic islets (Annicotte et al 2009). This observation could explain in part why beta-cells from suckling rats show low proliferation rates (tested by Ki67 immunofluorescence, data not shown) despite their high expression of cell-cycle-related genes, indicating that the beta-cells' proliferative capability is inversely correlated with the basal robust insulin secretion and the glucosestimulated insulin secretion functions.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome landmarks of the functional maturity of rat beta-cells, from lactation to adulthood

Larqué

Velasco

Barajas‐Olmos

et al. 2016

Journal of Molecular Endocrinology

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Research on the postnatal development of pancreatic beta-cells has become an important subject in recent years. Understanding the mechanisms that govern beta-cell postnatal maturation could bring new opportunities to therapeutic approaches for diabetes. The weaning period consists of a critical postnatal window for structural and physiologic maturation of rat beta-cells. To investigate transcriptome changes involved in the maturation of beta-cells neighboring this period, we performed microarray analysis in fluorescence-activated cell-sorted (FACS) beta-cell-enriched populations. Our results showed a variety of gene sets including those involved in the integration of metabolism, modulation of electrical activity, and regulation of the cell cycle that play important roles in the maturation process. These observations were validated using reverse hemolytic plaque assay, electrophysiological recordings, and flow cytometry analysis. Moreover, we suggest some unexplored pathways such as sphingolipid metabolism, insulin-vesicle trafficking, regulation of transcription/transduction by miRNA-30, trafficking proteins, and cell cycle proteins that could play important roles in the process mentioned above for further investigation. ResearchFunctional maturation of rat beta-cells c larqué and others 57:1

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“…In this sense, the CDK4-RB-E2F axis and other cell cycle components have acquired a main role in the control of insulin secretion by pancreatic β-cells [2,3], of oxidative metabolism [4] and of adipogenesis [5][6][7][8].…”

Section: Commentarymentioning

confidence: 99%

CDKs: Much More Than Just the Control of Cell Cycle Progression

Escoté¹

2014

J Cell Sci Ther

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Lee and colleagues have shown that CDK4 plays a central role in glucose homeostasis. Insulin activates cyclin D1-CDK4, leading to a decrease in circulating glucose as a consequence of the down-regulation of main genes involved in liver gluconeogenesis. CommentaryIn recent years, our knowledge of CDK regulation has improved significantly and is no longer restricted to just its role in the control of cell cycle progression. Cyclin-dependent kinases (CDKs) are serine/ threonine protein kinases that are associated with their specific partners, cyclins which phosphorylate their protein targets. Thus, the cyclin-CDK complex works as a holoenzyme. The control of cell cycle progression by cyclin-CDK complexes was first studied several years ago, in the context of high proliferation rates and cancer. Understanding how CDKs function was one of the main aims of these studies, as the loss of this regulation can alter cell proliferation rates which, in the worst case scenario, may translate into malignant tumours.The cell cycle is mainly divided into G1, S, G2, and M phases, and transition between these phases is strongly controlled. Transition from G1 to S is tightly regulated and depends on the activity of the G1 phase cyclin-CDK complexes, where CDK can be CDK4 or CDK6 and is associated with G1 D-type cyclins (D1, D2 and D3). In addition, there is an upper-level control of the activity of cyclin-CDK complexes determined by the presence or absence of two families of CDK inhibitors (CKIs), INK4 proteins and the Cip/Kip family, respectively. When the G1 phase cyclin-CDK complexes are active, they regulate the transition to the S phase by a direct phosphorylation of the retinoblastoma protein (Rb). Rb hyperphosphorylation mediates the release of the E2F transcription factor, allowing its transit to the nucleus, where it can promote the transcription of several genes involved in cell cycle progression, apoptosis, and DNA synthesis [1].Besides their well-described role in the control of cell cycle progression, in recent years a new role for CDKs has emerged beyond the context of cell cycle progression, as a master regulator of metabolism. In this sense, the CDK4-RB-E2F axis and other cell cycle components have acquired a main role in the control of insulin secretion by pancreatic β-cells [2,3], of oxidative metabolism [4] and of adipogenesis [5][6][7][8].Much more recently, a unique study designed by the Puigserver group [9] demonstrated that CDK4 plays a central role in glucose homeostasis, specifically in liver gluconeogenesis. Briefly, insulin activates AKT (also known as PKB) through a cascade of correlative phosphorylation with the insulin receptor, insulin receptor substrates, PI3K and finally PDK1 (Figure 1). Once AKT is activated, AKT phosphorylates several substrates, among them, Glycogen synthase kinase 3 (GSK3), at Ser 21 in α subunit and at Ser 9 in β subunit, resulting in the inhibition of GSK3 kinase activity [10][11][12][13]. GSK3 is a well-conserved kinase, originally identified as an enzyme that regulat...

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The CDK4–pRB–E2F1 pathway controls insulin secretion

Cited by 120 publications

References 29 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

Transcriptome landmarks of the functional maturity of rat beta-cells, from lactation to adulthood

CDKs: Much More Than Just the Control of Cell Cycle Progression

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