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

Erythropoietin (Epo), stem cell factor (SCF), and insulin-like growth facto r-1 (IGF-1) are key regulators of erythroid cell proliferation and differen tiation. To understand the mechanisms of generation of signals by each of t hese growth factors, we determined the activation of the PI3-kinase/Akt pat hway during proliferation and differentiation of primary human erythroid pr ogenitors. 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 phosphory lation of a member of the Forkhead family (FH) of transcription factors FKHRL1, downstream of ac tivation of the Akt kinase. Such Epo-dependent activation of FKHRL1 apparen tly regulates the generation of Epo-dependent antiapoptotic signals as evid enced by the induction of apoptosis of erythroid progenitors during treatme nt of cells with the PI3-kinase (PI3K) inhibitor LY294002. Thus, the PI3B/A kt/FKHRL1 pathway is essential for inhibition of apoptosis in response to E po and SCF, while the IGF-1 receptor utilizes a different pathway. (C) Acad emic Press.