Forkhead Transcription Factor FKHR-L1 Modulates Cytokine-Dependent Transcriptional Regulation of p27KIP1

• DOI: 10.1128/mcb.20.24.9138-9148.2000
• Publication Date: 2002-07-27T10:06:23Z
• Authors: Pascale F. Dijkers; Rene H. Medema; Cornelieke Pals; Lolita Banerji; N. Shaun B. Thomas; Eric W.-F. Lam; Boudewijn M. T. B...; Jan A. M. Raaijma...; Jan-Willem J. Lam...; Leo Koenderman; Paul J. Coffer
• Keywords: Ectopic expression

Interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor regulate the survival, proliferation, differentiation of hematopoietic lineages. Phosphatidylinositol 3-kinase (PI3K) has been implicated in regulation these processes. Here we investigate molecular mechanism by which PI3K regulates cytokine-mediated proliferation survival murine pre-B-cell line Ba/F3. IL-3 was found to repress expression cyclin-dependent kinase inhibitor p27KIP1 through activation PI3K, this occurs at level transcription. This transcriptional modulation forkhead transcription FKHR-L1, inhibited FKHR-L1 activity a PI3K-dependent manner. We have generated Ba/F3 cell lines expressing tamoxifen-inducible active mutant [FKHR-L1(A3):ER*]. Tamoxifen-mediated FKHR-L1(A3):ER* resulted striking increase promoter mRNA protein levels as well induction apoptotic program. The appears be critical since mere ectopic sufficient induce apoptosis. Moreover, increased cytokine-starved bone marrow-derived stem cells from null-mutant mice compared that wild-type mice. Taken together, observations indicate inhibition p27KIP1transcription PI3K-induced phosphorylation provides novel regulating proliferation.