The FoxO/Bcl-6/cyclin D2 pathway mediates metabolic and growth factor stimulation of proliferation in Min6 pancreatic beta-cells.
Lack of nutrients and growth factors activates FoxO transcription factors in pancreatic beta-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 beta-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.
Glauser
Dominique A
DA
Medical Faculty, University of Geneva, Switzerland.
Schlegel
Werner
W
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056742:Cyclin D2 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter / Q000235:genetics / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000235:genetics / Q000502:physiology; D051379:Mice; D051560:Proto-Oncogene Proteins c-bcl-6; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
C490010:Bcl6 protein, mouse; D056742:Cyclin D2; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051560:Proto-Oncogene Proteins c-bcl-6