Martin SA, Ouchi T

Apoptosis is implemented by death machinery that involves the caspase family of proteins, under the condition of a variety of stresses. Previous studies have shown that mouse embryonic stem cells deficient for caspase-3 are resistant to UV-induced apoptosis and that the active form of caspase-3 translocates to the nucleus. It ...

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has also been shown that the breast cancer tumor suppressor, BRCA1, is phosphorylated on Ser1423 and Ser1524 by the ataxia telangiectasia mutated-related kinase (ATR) after UV damage. Here, we show that activation of caspase-3 by UV is abrogated in BRCA1-mutated SNU251 and HCC1937 cells but was restored by reexpressing wild-type (wt) BRCA1, but not phosphorylation-deficient BRCA1Ser1423Ala/Ser1524Ala (BRCA1(S1423/1524A)). In SNU251 cells expressing BRCA1(S1423/1524A), the inhibitory interaction between X-linked inhibitor of apoptosis protein (XIAP) and caspase-9 remains intact after UV, compared with cells expressing wt BRCA1. We determined that XIAP and BRCA1 interact and upon phosphorylation this complex is disrupted. Nuclear translocation of active caspase-3 is detected only when wt BRCA1 is reexpressed. Consistent with this, Rad21, a known substrate of caspase-3, is cleaved only when wt BRCA1 is expressed in vivo. These results propose a model that inhibition of BRCA1 phosphorylation leads to the abrogation of a specific form of apoptosis that is mediated by caspase-3.

Date: Dec. 01, 2005

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