The FoxO/Bcl-6/cyclin D2 pathway mediates metabolic and growth factor stimulation of proliferation in Min6 pancreatic β-cells

摘要

Lack of nutrients and growth factors activates FoxO transcription factors in pancreatic β-cells, whereas PI3K/Akt-dependent inactivation of FoxO favors proliferation. To address the link between FoxO and cell cycle control, we deprived Min6 cells of serum and glucose which activated FoxO and inhibited prolifera-tion. Concomitantly, expression of the transcriptional repressor Bcl-6 was stimulated, whereas cyclin D2 was lowered. Gain of function approaches indicated that FoxO activation was sufficient to activate bcl-6 transcription, while Bcl-6 repressed cyclin D2 transcription and proliferation. Thus, in pancreatic β-cells, the FoxO/Bcl6/cyclin D2 pathway connects nutrient and growth factor status to cell cycle control, and may therefore be considered for its therapeutic potential in diabetes.