TGF-β Signaling Regulates Pancreatic β-Cell Proliferation through Control of Cell Cycle Regulator p27 Expression

Proliferation of pancreatic beta-cells is an important mechanism underlying beta-cell mass adaptation to metabolic demands. Increasing beta-cell mass by regeneration may ameliorate or correct both type 1 and type 2 diabetes, which both result from inadequate production of insulin by beta-cells of the pancreatic islet. Transforming growth factor beta (TGF-beta) signaling is essential for fetal development and growth of pancreatic islets. In this study, we exposed HIT-T15, a clonal pancreatic beta-cell line, to TGF-beta signaling. We found that inhibition of TGF-beta signaling promotes proliferation of the cells significantly, while TGF-beta signaling stimulation inhibits proliferation of the cells remarkably. We confirmed that this proliferative regulation by TGF-beta signaling is due to the changed expression of the cell cycle regulator p27. Furthermore, we demonstrated that there is no observed effect on transcriptional activity of p27 by TGF-beta signaling. Our data show that TGF-beta signaling mediates the cell-cycle progression of pancreatic beta-cells by regulating the nuclear localization of CDK inhibitor, p27. Inhibition of TGF-beta signaling reduces the nuclear accumulation of p27, and as a result this inhibition promotes proliferation of beta-cells.