Contribution of Bcl-2 phosphorylation to Bak binding and drug resistance.
Cancer Res
; 73(23): 6998-7008, 2013 Dec 01.
Article
en En
| MEDLINE
| ID: mdl-24097825
ABSTRACT
Bcl-2 is phosphorylated on Ser(70) after treatment of cells with spindle poisons. On the basis of effects observed in cells overexpressing Bcl-2 S70E or S70A mutants, various studies have concluded that Ser(70) phosphorylation either enhances or diminishes Bcl-2 function. In the present study, the ability of phosphorylated Bcl-2, as well as the S70E and S70A mutants, to bind and neutralize proapoptotic Bcl-2 family members under cell-free conditions and in intact cells was examined in an attempt to resolve this controversy. Surface plasmon resonance indicated that phosphorylated Bcl-2, Bcl-2 S70E, and Bcl-2 S70A exhibit enhanced binding to Bim and Bak compared with unmodified Bcl-2. This enhanced binding reflected a readily detectable conformation change in the loop domain of Bcl-2. Furthermore, Bcl-2 S70E and S70A bound more Bak and Bim than wild-type Bcl-2 in pull-downs and afforded greater protection against several chemotherapeutic agents. Importantly, binding of endogenous Bcl-2 to Bim also increased during mitosis, when Bcl-2 is endogenously phosphorylated, and disruption of this mitotic Bcl-2/Bim binding with navitoclax or ABT-199, like Bcl-2 downregulation, enhanced the cytotoxicity of paclitaxel. Collectively, these results provide not only a mechanistic basis for the enhanced antiapoptotic activity of phosphorylated Bcl-2, but also an explanation for the ability of BH3 mimetics to enhance taxane sensitivity.
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MEDLINE
Asunto principal:
Proteína Quinasa CDC2
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Resistencia a Antineoplásicos
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Proteínas Proto-Oncogénicas c-bcl-2
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Proteína Destructora del Antagonista Homólogo bcl-2
Idioma:
En
Revista:
Cancer Res
Año:
2013
Tipo del documento:
Article