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Rapidly dividing cells such as tumor cells are susceptible to DNA damage that then induces apoptosis. As a result, DNA-damaging chemicals such as cisplatin are used as anticancer treatments. How the majority of nontumor cells survive chemotherapy has been mysterious. The trivial explanation is that the cells are growth-arrested and thus less susceptible to DNA-damaging agents. But a more precise explanation is put forth in a new article by Benjamin Deverman, Steven Weintraub (Washington University, St. Louis, MO), and colleagues, who have identified an antiapoptotic activity necessary to keep damaged but nondividing cells alive.
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5 \& {+ `5 F! ] m; RThe proapoptotic activity that allows tumor cells to die is an unusual modification of the antiapoptotic protein Bcl-xL caused by DNA-damaging agents. This modification, deamidation of two asparagine residues, inactivated Bcl-xL, thereby allowing cell death to proceed. Growth-arrested cells escaped apoptosis by blocking deamidation. To prevent deamidation, cells needed Rb, a tumor suppressor protein that inhibits cell cycle progression. Because tumor cells lack Rb, and cycling cells down-regulate Rb, they are more sensitive to DNA-damaging agents. "Deamidation is like a checkpoint," says Weintraub. "If you undergo DNA damage in the absence of Rb, then cells are susceptible to death."
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Deverman, B., et al. 2002. Cell. 111:51–62.(Bcl-xL modification by cisplatin is bloc) |
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发表于 2009-3-6 00:07
发表于 2015-6-4 20:41
