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

Abstract

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 proliferation. 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.

Keywords::

• Pancreatic β-cell proliferation
• FoxO
• glucose
• Bcl-6
• cyclin D2

Acknowledgements

We would like to acknowledge Isabelle Piuz, Marine Steidel and Abbas Massiha for technical assistance. We are grateful to: Anne Brunet for the gift of the pECE/FoxO3aTM, pECE/FoxO3aTMδCT, and pGL3/FHRE plasmids; Akiyoshi Fukamizu for the gift of the pcDNA3/Foxo1(3KR) plasmid; Takahiro Hara for the gift of the pGL3/cyclin D2 plasmid; Herbert Morse for the gift of the pGL3/Bcl-6 plasmid; Paul Ko Ferrigno and Simon Wagner for the gift of pcDNA3/Bcl-6. Financial support was from Swiss National Foundation, grants No 3100A0-102147/1 to W.S. and from the Fondation pour Recherches Médicales, Geneva.

Declaration of interest: The authors declare no conflict of interest.