10944433

pubmed:Citation

1

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.

eng

IM

MEDLINE

0006-291X

Copyright 2000 Academic Press.

18

NLM

16-9

pubmed-meshheading:10944433-Apoptosis, pubmed-meshheading:10944433-Caspase 3, pubmed-meshheading:10944433-Caspases, pubmed-meshheading:10944433-Cell Differentiation, pubmed-meshheading:10944433-Cells, Cultured, pubmed-meshheading:10944433-Chromones, pubmed-meshheading:10944433-DNA-Binding Proteins, pubmed-meshheading:10944433-Enzyme Activation, pubmed-meshheading:10944433-Erythroid Precursor Cells, pubmed-meshheading:10944433-Erythropoietin, pubmed-meshheading:10944433-Forkhead Transcription Factors, pubmed-meshheading:10944433-Humans, pubmed-meshheading:10944433-Insulin-Like Growth Factor I, pubmed-meshheading:10944433-Morpholines, pubmed-meshheading:10944433-Phosphatidylinositol 3-Kinases, pubmed-meshheading:10944433-Phosphorylation, pubmed-meshheading:10944433-Poly(ADP-ribose) Polymerases, pubmed-meshheading:10944433-Protein-Serine-Threonine Kinases, pubmed-meshheading:10944433-Proto-Oncogene Proteins, pubmed-meshheading:10944433-Proto-Oncogene Proteins c-akt, pubmed-meshheading:10944433-Signal Transduction, pubmed-meshheading:10944433-Sirolimus, pubmed-meshheading:10944433-Stem Cell Factor, pubmed-meshheading:10944433-Transcription Factors

Activation of the Akt/FKHRL1 pathway mediates the antiapoptotic effects of erythropoietin in primary human erythroid progenitors.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't