期刊
BLOOD
卷 97, 期 5, 页码 1289-1297出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.V97.5.1289
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- NCI NIH HHS [R01CA78443] Funding Source: Medline
- NIGMS NIH HHS [GM53165] Funding Source: Medline
BAD is a proapoptotic member of the BCL-2 family of proteins, which play a major role in regulating apoptosis in cytokine-dependent hematopoietic cells. The function of BAD is regulated by reversible phosphorylation. De privation of survival factors induces BAD dephosphorylation, resulting in apoptosis, Serine-threonine phosphatase activity de phosphorylated BAD in interleukin-3-dependent FL5.12 lymphoid cells. Inhibition of PP2A activity by treatment of cells with PP2A-selective inhibitors, okadaic acid and fostriecin, prevented BAD dephosphorylation in these cells. Conversely, BAD dephosphorylation was not inhibited by the PP1-selective inhibitor tautomycin, In cell-free extracts, BAD phosphatase activity was also inhibited by the PP2A-selective inhibitors okadaic acid and fostriecin, but not by the PP1-specific protein inhibitor 1-2. Dissociation of 14-3-3 from BAD was a prerequisite for BAD dephosphorylation in vitro, suggesting a mechanism by which 14-3-3 can regulate the activation of the proapoptotic function of BAD in vivo. Significantly, the inhibition of BAD phosphatase activity rescued cell death induced by survival factor withdrawal in FL5.12 cells expressing wildtype BAD but not phosphorylation-defective mutant BAD. These data indicate that PP2A, or a PP2A-like enzyme, dephosphorylates BAD and, in conjunction with 14-3-3, modulates cytokine-mediated survival, (Blood, 2001;97:1289-1297) (C) 2001 by The American Society of Hematology.
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