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Molecular and Cellular Biology, December 2000, p. 9138-9148, Vol. 20, No. 24
Departments of Pulmonary Diseases1
and Hematology,2 University Medical
Center, 3584 CX Utrecht, and Department of Physiological
Chemistry and Center for Biomedical Genetics, University of Utrecht,
3584 CG Utrecht,5 The Netherlands, and
Ludwig Institute for Cancer Research and Section of Virology
and Cell Biology, Imperial College School of Medicine, St. Mary's
Campus,3 and Department of
Haematological Medicine, Guy's, King's and St. Thomas' School of
Medicine and Dentistry, King's Denmark Hill
Campus,4 London, United Kingdom
Received 12 May 2000/Returned for modification 21 June
2000/Accepted 12 September 2000
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 p27KIP1
transcription through PI3K-induced FKHR-L1 phosphorylation provides a
novel mechanism of regulating cytokine-mediated survival and proliferation.
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Forkhead Transcription Factor FKHR-L1 Modulates
Cytokine-Dependent Transcriptional Regulation of
p27KIP1
*
Corresponding author. Mailing address: Department of
Pulmonary Diseases, University Medical Center, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Phone: 31-30-2507134. Fax:
31-30-2505414. E-mail: P.Coffer{at}hli.azu.nl.
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