RT Journal Article SR Electronic T1 Forkhead Transcription Factor FKHR-L1 Modulates Cytokine-Dependent Transcriptional Regulation of p27KIP1 JF Molecular and Cellular Biology JO Mol. Cell. Biol. FD American Society for Microbiology SP 9138 OP 9148 DO 10.1128/MCB.20.24.9138-9148.2000 VO 20 IS 24 A1 Dijkers, Pascale F. A1 Medema, Rene H. A1 Pals, Cornelieke A1 Banerji, Lolita A1 Thomas, N. Shaun B. A1 Lam, Eric W.-F. A1 Burgering, Boudewijn M. T. A1 Raaijmakers, Jan A. M. A1 Lammers, Jan-Willem J. A1 Koenderman, Leo A1 Coffer, Paul J. YR 2000 UL http://mcb.asm.org/content/20/24/9138.abstract AB Interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor regulate the survival, proliferation, and differentiation of hematopoietic lineages. Phosphatidylinositol 3-kinase (PI3K) has been implicated in the regulation of these processes. Here we investigate the molecular mechanism by which PI3K regulates cytokine-mediated proliferation and survival in the murine pre-B-cell line Ba/F3. IL-3 was found to repress the expression of the cyclin-dependent kinase inhibitor p27KIP1 through activation of PI3K, and this occurs at the level of transcription. This transcriptional regulation occurs through modulation of the forkhead transcription factor FKHR-L1, and IL-3 inhibited FKHR-L1 activity in a PI3K-dependent manner. We have generated Ba/F3 cell lines expressing a tamoxifen-inducible active FKHR-L1 mutant [FKHR-L1(A3):ER*]. Tamoxifen-mediated activation of FKHR-L1(A3):ER* resulted in a striking increase in p27KIP1 promoter activity and mRNA and protein levels as well as induction of the apoptotic program. The level of p27KIP1 appears to be critical in the regulation of cell survival since mere ectopic expression of p27KIP1 was sufficient to induce Ba/F3 apoptosis. Moreover, cell survival was increased in cytokine-starved bone marrow-derived stem cells from p27KIP1 null-mutant mice compared to that in cells from wild-type mice. Taken together, these observations indicate that inhibition of p27KIP1transcription through PI3K-induced FKHR-L1 phosphorylation provides a novel mechanism of regulating cytokine-mediated survival and proliferation.