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Cytokine mediated suppression of TF‐1 apoptosis requires PI3K activation and inhibition of Bim expression
Author(s) -
Rosas Marcela,
Birkenkamp Kim U.,
Lammers Jan-Willem J.,
Koenderman Leo,
Coffer Paul J.
Publication year - 2005
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2004.11.074
Subject(s) - microbiology and biotechnology , pi3k/akt/mtor pathway , protein kinase b , apoptosis , cytokine , signal transduction , downregulation and upregulation , cancer research , haematopoiesis , biology , effector , suppressor of cytokine signalling , chemistry , immunology , socs3 , stem cell , biochemistry , stat3 , gene
Phosphatidylinositol 3‐kinase (PI3K) and its effector protein kinase B (PKB/c‐akt) have been implicated as critical mediators of cytokine‐induced survival signals. In this study, we have utilized an IL‐5 dependent hematopoietic cell line (TF‐1) to investigate the signaling events involved in cytokine‐dependent erythroblast survival. We demonstrate that IL‐5 rescues TF‐1 cells from apoptosis through a PI3K/PKB‐dependent signaling pathway. Cytokine‐withdrawal leads to activation of the Forkhead transcription factor FOXO3a and subsequent expression of the pro‐apoptotic Bcl‐2 family member Bim. Bim is itself sufficient to induce apoptosis in these cells. Importantly, activation of an inducible active FOXO3a mutant is alone sufficient for upregulation of Bim expression and induction of apoptosis. These data define a mechanism by which survival factors inhibit the default apoptotic pathway and can regulate TF‐1 erythroblast survival.