Activation of the Akt/FKHRL1 pathway mediates the antiapoptotic effects of erythropoietin in primary human erythroid progenitors.
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.
Uddin
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Section of Hematology/Oncology, University of Illinois at Chicago, Chicago, Illinois, 60607, USA.
Kottegoda
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S
Stigger
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D
Platanias
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LC
Wickrema
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A
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology*; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D019089:Stem Cell Factor / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*
D053148:Caspase 3; D020169:Caspases; D002867:Chromones; D004268:DNA-Binding Proteins; D004921:Erythropoietin; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007334:Insulin-Like Growth Factor I; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D019089:Stem Cell Factor; D014157:Transcription Factors; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human; C505407:CASP3 protein, human