Cyclin D1 activation through ATF‐2 in Reg‐induced pancreatic β‐cell regeneration

Regenerating gene product (Reg) is induced in pancreatic β‐cells and acts as an autocrine/paracrine growth factor for regeneration via a cell surface Reg receptor. However, the manner by which Reg induces β‐cell regeneration was unknown. In the present study, we found that Reg increased phospho‐ATF‐2, which binds to −57 to −52 of the cyclin D1 gene to activate the promoter. The Reg/ATF‐2‐induced cyclin D1 promoter activation was attenuated by PI(3)K inhibitors such as LY294002 and wortmannin. In Reg knockout mouse islets, the levels of phospho‐ATF‐2, cyclin D1, and phospho‐Rb were greatly decreased. These results indicate that the Reg–Reg receptor system stimulates the PI(3)K/ATF‐2/cyclin D1 signaling pathway to induce β‐cell regeneration.