Reciprocal control of Forkhead box O 3a and c-Myc via the phosphatidylinositol 3-kinase pathway coordinately regulates p27Kip1 levels.
B cell receptor (BCR) engagement of murine WEHI 231 immature B lymphoma cells leads sequentially to a drop in NF-kappa B and c-Myc, and induction of the p27(Kip1) cyclin-dependent kinase inhibitor, which promotes growth arrest and apoptosis. BCR engagement was recently shown to induce a drop in phosphatidylinositol 3-kinase (PI3K)/Akt signaling, preceding the increase in p27. As induction of p27 is due to an increase in gene transcription, we investigated the role of the Forkhead box O (FOXO) transcription factor family, which has been shown to potently induce p27 promoter activity. We demonstrate that pharmacologic inhibitors of PI3K or BCR engagement lead to decreased inactive cytoplasmic levels and increased active functional nuclear FOXO3a. In contrast, inhibition of PI3K/Akt signaling decreased the levels of NF-kappa B and c-Myc, which has been shown to repress p27 promoter activity. To test the effects of ectopic c-Myc on endogenous p27 levels, WEHI 231 cells stably expressing c-Myc or empty vector DNA were prepared. Ectopic c-Myc blocked the induction of p27 expression upon either inhibition of PI3K or BCR engagement. Thus, p27(Kip1) is coordinately regulated via two arms of a signaling pathway that are inversely controlled upon inhibition of PI3K: induction of the activator FOXO3a and down-regulation of the repressor c-Myc.
Chandramohan
Vidyalakshmi
V
Department of Biochemistry, Boston University Medical School, Boston, MA 02118, USA.
Jeay
Sébastien
S
Pianetti
Stefania
S
Sonenshein
Gail E
GE
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000378:metabolism*; D016923:Cell Death / Q000276:immunology; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007075:Immunoglobulin M / Q000276:immunology; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000378:metabolism*
D000888:Antibodies, Anti-Idiotypic; D018797:Cell Cycle Proteins; D002867:Chromones; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004791:Enzyme Inhibitors; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007075:Immunoglobulin M; D009025:Morpholines; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C493961:Cdkn1b protein, mouse; C474033:FoxO3 protein, mouse; C044203:anti-IgM; C413374:p27 antigen; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one