ArticleMolecular endocrinology (Baltimore, Md.)2009
Cyclin D2 protein stability is regulated in pancreatic beta-cells.
Article in Molecular endocrinology (Baltimore, Md.), 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 50 citations in OpenAlex.
- Article
- Harnessing beta-cell replication: advancing molecular insights to regenerative therapies in diabetes.Frontiers in endocrinology · 2025Review
- Nuclear focal adhesion kinase induces APC/C activator protein CDH1-mediated cyclin-dependent kinase 4/6 degradation and inhibits melanoma proliferation.The Journal of biological chemistry · 2022Article
- GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health.Nature communications · 2021Observational
- Article
- Recurrent cyclin D2 mutations in myeloid neoplasms.Leukemia · 2017Article
- GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in βIRKO mice.Diabetologia · 2017Article
- β Cells Persist in T1D Pancreata Without Evidence of Ongoing β-Cell Turnover or Neogenesis.The Journal of clinical endocrinology and metabolism · 2017Article
- Incretin Therapies Do Not Expand β-Cell Mass or Alter Pancreatic Histology in Young Male Mice.Endocrinology · 2017Article
- Cyclin D2 is sufficient to drive β cell self-renewal and regeneration.Cell cycle (Georgetown, Tex.) · 2017Article
- Epidermal Growth Factor Receptor Signaling Regulates β Cell Proliferation in Adult Mice.The Journal of biological chemistry · 2016Article
- Islet biology, the CDKN2A/B locus and type 2 diabetes risk.Diabetologia · 2016Review
- Extreme obesity induces massive beta cell expansion in mice through self-renewal and does not alter the beta cell lineage.Diabetologia · 2016Article
- Glucose Induces Mouse β-Cell Proliferation via IRS2, MTOR, and Cyclin D2 but Not the Insulin Receptor.Diabetes · 2016Article
- The cell cycle as a brake for β-cell regeneration from embryonic stem cells.Stem cell research & therapy · 2016Review
- M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- D-type Cyclins are important downstream effectors of cytokine signaling that regulate the proliferation of normal and neoplastic mammary epithelial cells.Molecular and cellular endocrinology · 2014Review
- GATA factors promote ER integrity and β-cell survival and contribute to type 1 diabetes risk.Molecular endocrinology (Baltimore, Md.) · 2014Article
- Article
- Successful β cells islet regeneration in streptozotocin-induced diabetic baboons using ultrasound-targeted microbubble gene therapy with cyclinD2/CDK4/GLP1.Cell cycle (Georgetown, Tex.) · 2014Article
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 1 country.
Funding
Abstract
The molecular determinants of beta-cell mass expansion remain poorly understood. Cyclin D2 is the major D-type cyclin expressed in beta-cells, essential for adult beta-cell growth. We hypothesized that cyclin D2 could be actively regulated in beta-cells, which could allow mitogenic stimuli to influence beta-cell expansion. Cyclin D2 protein was sharply increased after partial pancreatectomy, but cyclin D2 mRNA was unchanged, suggesting posttranscriptional regulatory mechanisms influence cyclin D2 expression in beta-cells. Consistent with this hypothesis, cyclin D2 protein stability is powerfully regulated in fibroblasts. Threonine 280 of cyclin D2 is phosphorylated, and this residue critically limits D2 stability. We derived transgenic (tg) mice with threonine 280 of cyclin D2 mutated to alanine (T280A) or wild-type cyclin D2 under the control of the insulin promoter. Cyclin D2 T280A protein was expressed at much higher levels than wild-type cyclin D2 protein in beta-cells, despite equivalent expression of tg mRNAs. Cyclin D2 T280A tg mice exhibited a constitutively nuclear cyclin D2 localization in beta-cells, and increased cyclin D2 stability in islets. Interestingly, threonine 280-mutant cyclin D2 tg mice had greatly reduced beta-cell apoptosis, with suppressed expression of proapoptotic genes. Suppressed beta-cell apoptosis in threonine 280-mutant cyclin D2 tg mice resulted in greatly increased beta-cell area in aged mice. Taken together, these data indicate that cyclin D2 is regulated by protein stability in pancreatic beta-cells, that signals that act upon threonine 280 limit cyclin D2 stability in beta-cells, and that threonine 280-mutant cyclin D2 overexpression prolongs beta-cell survival and augments beta-cell mass expansion.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.