Loss of Hus1 sensitizes cells to etoposide-induced apoptosis by regulating BH3-only proteins.
Loss of Hus1 sensitizes cells to etoposide-induced apoptosis by regulating BH3-only proteins.
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DOI：
10.1038/onc.2008.336
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发表时间：
2008-12-11
期刊：
影响因子：
8
通讯作者：
Wang, H-G
中科院分区：
文献类型：
--
作者：
Meyerkord, C. L.;Takahashi, Y.;Araya, R.;Takada, N.;Weiss, R. S.;Wang, H-G
The Rad9-Rad1-Hus1 (9-1-1) cell cycle checkpoint complex plays a key role in the DNA damage response. Cells with a defective 9-1-1 complex have been shown to be sensitive to apoptosis induced by certain types of genotoxic stress. However, the mechanism linking the loss of a functional 9-1-1 complex to the cell death machinery has yet to be determined. Here, we report that etoposide treatment dramatically upregulates the BH3-only proteins, Bim and Puma, in Hus1-deficient cells. Inhibition of either Bim or Puma expression in Hus1-knockout cells confers significant resistance to etoposide-induced apoptosis, while knockdown of both proteins results in further resistance, suggesting that Bim and Puma cooperate in sensitizing Hus1-deficient cells to etoposide treatment. Moreover, we found that Rad9 collaborates with Bim and Puma to sensitize Hus1-deficient cells to etoposide-induced apoptosis. In response to DNA damage, Rad9 localizes to chromatin in Hus1-wild-type cells, whereas in Hus1-deficient cells it is predominantly located in the cytoplasm where it binds to Bcl-2. Taken together, these results suggest that loss of Hus1 sensitizes cells to etoposide-induced apoptosis, not only by inducing Bim and Puma expression, but also by releasing Rad9 into the cytosol to augment mitochondrial apoptosis.
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影响因子：
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作者：
Burtelow, MA;Roos-Mattjus, PMK;Karnitz, LM
通讯作者：
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影响因子：
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DOI：
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