PTEN controls β-cell regeneration in aged mice by regulating cell cycle inhibitor p16ink4a
Autor: | Ismail H. Al-Abdullah, Vivian Medina, Ni Zeng, Fouad Kandeel, Bangyan L. Stiles, Richa Aggarwal, Lina He, Joseph W. Stiles, Danny Abad, Jennifer-Ann Bayan, Kai-Ting Yang, Beth M. Palian, Deborah L. Johnson, Xiaogang Hou |
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Rok vydání: | 2013 |
Předmět: |
Aging
Down-Regulation Biology Article Mice Downregulation and upregulation Insulin-Secreting Cells Tensin PTEN Animals Humans Cyclin D1 Enhancer of Zeste Homolog 2 Protein E2F PI3K/AKT/mTOR pathway Cyclin-Dependent Kinase Inhibitor p16 Cell Proliferation Cell growth Cell Cycle PTEN Phosphohydrolase Polycomb Repressive Complex 2 Cell Biology Cell cycle DNA Methylation Cell biology Up-Regulation biology.protein Cancer research Cell aging Cyclin-Dependent Kinase Inhibitor p27 Gene Deletion Signal Transduction |
Zdroj: | Aging cell. 12(6) |
ISSN: | 1474-9726 |
Popis: | Tissue regeneration diminishes with age, concurrent with declining hormone levels including growth factors such as insulin-like growth factor-1 (IGF-1). We investigated the molecular basis for such decline in pancreatic β-cells where loss of proliferation occurs early in age and is proposed to contribute to the pathogenesis of diabetes. We studied the regeneration capacity of β-cells in mouse model where PI3K/AKT pathway downstream of insulin/IGF-1 signaling is upregulated by genetic deletion of Pten (phosphatase and tensin homologue deleted on chromosome 10) specifically in insulin-producing cells. In this model, PTEN loss prevents the decline in proliferation capacity in aged β-cells and restores the ability of aged β-cells to respond to injury-induced regeneration. Using several animal and cell models where we can manipulate PTEN expression, we found that PTEN blocks cell cycle re-entry through a novel pathway leading to an increase in p16(ink4a), a cell cycle inhibitor characterized for its role in cellular senescence/aging. A downregulation in p16(ink4a) occurs when PTEN is lost as a result of cyclin D1 induction and the activation of E2F transcription factors. The activation of E2F transcriptional factors leads to methylation of p16(ink4a) promoter, an event that is mediated by the upregulation of polycomb protein, Ezh2. These analyses establish a novel PTEN/cyclin D1/E2F/Ezh2/p16(ink4a) signaling network responsible for the aging process and provide specific evidence for a molecular paradigm that explain how decline in growth factor signals such as IGF-1 (through PTEN/PI3K signaling) may control regeneration and the lack thereof in aging cells. |
Databáze: | OpenAIRE |
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