Document Detail


Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1).
MedLine Citation:
PMID:  11094066     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 p27(KIP1) 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 p27(KIP1) promoter activity and mRNA and protein levels as well as induction of the apoptotic program. The level of p27(KIP1) appears to be critical in the regulation of cell survival since mere ectopic expression of p27(KIP1) was sufficient to induce Ba/F3 apoptosis. Moreover, cell survival was increased in cytokine-starved bone marrow-derived stem cells from p27(KIP1) null-mutant mice compared to that in cells from wild-type mice. Taken together, these observations indicate that inhibition of p27(KIP1) transcription through PI3K-induced FKHR-L1 phosphorylation provides a novel mechanism of regulating cytokine-mediated survival and proliferation.
Authors:
P F Dijkers; R H Medema; C Pals; L Banerji; N S Thomas; E W Lam; B M Burgering; J A Raaijmakers; J W Lammers; L Koenderman; P J Coffer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular and cellular biology     Volume:  20     ISSN:  0270-7306     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2000 Dec 
Date Detail:
Created Date:  2000-12-13     Completed Date:  2001-01-11     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  9138-48     Citation Subset:  IM    
Affiliation:
Departments of Pulmonary Diseases, The Netherlands.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects,  genetics
B-Lymphocytes / cytology,  metabolism
Cell Cycle Proteins*
Cell Line
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases / antagonists & inhibitors
Cytokines / metabolism*
DNA-Binding Proteins / antagonists & inhibitors,  genetics,  metabolism*
Enzyme Inhibitors / metabolism*,  pharmacology
Eosinophils / drug effects,  metabolism
Forkhead Transcription Factors
Gene Expression Regulation
Genes, Reporter / genetics
Hematopoietic Stem Cells / cytology,  metabolism
Humans
Hydroxytestosterones / pharmacology
Interleukin-3 / genetics,  metabolism*
Mice
Microtubule-Associated Proteins / genetics*,  metabolism
Mutation
PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinases / metabolism*
Phosphoric Monoester Hydrolases / genetics,  metabolism
Promoter Regions, Genetic / drug effects
RNA / metabolism
Signal Transduction
Sirolimus / pharmacology
Tamoxifen / pharmacology
Transcription Factors / antagonists & inhibitors,  genetics,  metabolism*
Transcription, Genetic / genetics*
Tumor Suppressor Proteins*
Chemical
Reg. No./Substance:
0/Cdkn1b protein, mouse; 0/Cell Cycle Proteins; 0/Cytokines; 0/DNA-Binding Proteins; 0/Enzyme Inhibitors; 0/FOXO1 protein, human; 0/Forkhead Transcription Factors; 0/Foxo1 protein, mouse; 0/Hydroxytestosterones; 0/Interleukin-3; 0/Microtubule-Associated Proteins; 0/Transcription Factors; 0/Tumor Suppressor Proteins; 10540-29-1/Tamoxifen; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 2141-17-5/4,17 beta-dihydroxy-4-androstene-3-one; 53123-88-9/Sirolimus; 63231-63-0/RNA; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.22/Cyclin-Dependent Kinases; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase
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