Document Detail

Activation of the Akt/FKHRL1 pathway mediates the antiapoptotic effects of erythropoietin in primary human erythroid progenitors.
MedLine Citation:
PMID:  10944433     Owner:  NLM     Status:  MEDLINE    
Erythropoietin (Epo), stem cell factor (SCF), and insulin-like growth factor-1 (IGF-1) are key regulators of erythroid cell proliferation and differentiation. To understand the mechanisms of generation of signals by each of these growth factors, we determined the activation of the PI3-kinase/Akt pathway during proliferation and differentiation of primary human erythroid progenitors. Our results demonstrate that PKB/Akt is activated by Epo and SCF, but not by IGF-1 in human primary erythroid progenitors. In addition, Epo treatment of erythroid progenitors induces phosphorylation of a member of the Forkhead family (FH) of transcription factors FKHRL1, downstream of activation of the Akt kinase. Such Epo-dependent activation of FKHRL1 apparently regulates the generation of Epo-dependent antiapoptotic signals as evidenced by the induction of apoptosis of erythroid progenitors during treatment of cells with the PI3-kinase (PI3K) inhibitor LY294002. Thus, the PI3K/Akt/FKHRL1 pathway is essential for inhibition of apoptosis in response to Epo and SCF, while the IGF-1 receptor utilizes a different pathway.
S Uddin; S Kottegoda; D Stigger; L C Platanias; A Wickrema
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Biochemical and biophysical research communications     Volume:  275     ISSN:  0006-291X     ISO Abbreviation:  Biochem. Biophys. Res. Commun.     Publication Date:  2000 Aug 
Date Detail:
Created Date:  2000-09-21     Completed Date:  2000-09-21     Revised Date:  2012-06-22    
Medline Journal Info:
Nlm Unique ID:  0372516     Medline TA:  Biochem Biophys Res Commun     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  16-9     Citation Subset:  IM    
Copyright Information:
Copyright 2000 Academic Press.
Section of Hematology/Oncology, University of Illinois at Chicago, Chicago, Illinois, 60607, USA.
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MeSH Terms
Apoptosis / drug effects*
Caspase 3
Caspases / metabolism
Cell Differentiation
Cells, Cultured
Chromones / pharmacology
DNA-Binding Proteins / metabolism*
Enzyme Activation / drug effects
Erythroid Precursor Cells / cytology,  drug effects*,  enzymology,  metabolism
Erythropoietin / pharmacology*
Forkhead Transcription Factors
Insulin-Like Growth Factor I / pharmacology
Morpholines / pharmacology
Phosphatidylinositol 3-Kinases / antagonists & inhibitors,  metabolism
Phosphorylation / drug effects
Poly(ADP-ribose) Polymerases / metabolism
Protein-Serine-Threonine Kinases*
Proto-Oncogene Proteins / metabolism*
Proto-Oncogene Proteins c-akt
Signal Transduction* / drug effects
Sirolimus / pharmacology
Stem Cell Factor / pharmacology
Transcription Factors / metabolism*
Grant Support
Reg. No./Substance:
0/Chromones; 0/DNA-Binding Proteins; 0/FOXO1 protein, human; 0/FOXO3 protein, human; 0/Forkhead Transcription Factors; 0/Morpholines; 0/Proto-Oncogene Proteins; 0/Stem Cell Factor; 0/Transcription Factors; 11096-26-7/Erythropoietin; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 53123-88-9/Sirolimus; 67763-96-6/Insulin-Like Growth Factor I; EC Polymerases; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC protein, human; EC Kinases; EC Proteins c-akt; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases

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