PTEN controls β‐cell regeneration in aged mice by regulating cell cycle inhibitor p16^ink4a

Abstract

SUMMARY 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 reentry through a novel pathway leading to an increase of p16ink4a, a cell cycle inhibitor characterized for its role in cellular senescence/aging. A downregulation in p16ink4a 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 p16ink4a promoter, an event that is mediated by the upregulation of polycomb protein, Ezh2. These analyses establish a novel PTEN/cyclin D1/E2F/Ezh2/p16ink4a signaling network responsible for the aging process and provide specific evidence for a molecular paradigm that explain how decline of growth factor signals such as IGF-1 (through PTEN/PI3K signaling) may control regeneration and the lack thereof in aging cells.

A Natural Androgen Receptor Antagonist Induces Cellular Senescence in Prostate Cancer Cells

“…However, the link between Akt and p16 expression remains unclear. Interestingly, a recent publication also linked p16 expression and Akt activity using several animal and cell models with modulated PTEN ( phosphatase and tensin homolog deleted from chromosome 10) expression, which regulates the Akt activity (30). The authors postulate a block of cell cycle reentry through a novel pathway, leading to an increase in p16.…”

MicroRNA-301a promotes cell proliferation via PTEN targeting in Ewing's sarcoma cells

“…PTEN plays a vital role in regulating the cell cycle and inhibiting cell growth and division (17,18). Recently, several reports demonstrated PTEN involvement in apoptosis in human hepatocellular carcinoma cells (19), and in cell proliferation, migration, and invasion in gastric cancer (20).…”

Mouse Insulin Cells Expressing an Inducible RIPCre Transgene Are Functionally Impaired

“…Although RipCreER mice were tested as controls, the effect of the mutation was evaluated on beta cells that underwent Cre-mediated recombination and were already suboptimal. Similar concerns are raised with studies in which RIPCreER mice were used for cell lineage analysis (17), clonal studies of beta cell development (18), insulin resistance (19), glucose sensing by beta cells (20); effects of hyperglycemia on islet morphology (21), changes in islet composition during pregnancy (22), beta cell proliferation (23,24), generation of new beta cells during regeneration (25), beta cell apoptosis (26), and for the analysis of the role of NeuroD, a transactivator of the insulin gene, in beta cell development (27). Moreover, results from classical studies using RIPCre mice for cell lineage analysis of alpha and beta cells during development (28) should also be reexamined, since the fate of abnormal RIPCre cells may be different from that of insulin cells that do not express the transgene.…”