Bcl-xL deamidation is a critical switch in the regulation of the response to DNA damage |
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Authors: | Deverman Benjamin E Cook Brian L Manson Scott R Niederhoff Robert A Langer Ellen M Rosová Ivana Kulans Laura A Fu Xiaoyun Weinberg Justin S Heinecke Jay W Roth Kevin A Weintraub Steven J |
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Affiliation: | Division of Urology, Department of Cell Biology and Physiology, School of Medicine, Washington University, 660 South Euclid Avenue, Campus Box 8052, Saint Louis, MO 63110, USA. |
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Abstract: | The therapeutic value of DNA-damaging antineoplastic agents is dependent upon their ability to induce tumor cell apoptosis while sparing most normal tissues. Here, we show that a component of the apoptotic response to these agents in several different types of tumor cells is the deamidation of two asparagines in the unstructured loop of Bcl-xL, and we demonstrate that deamidation of these asparagines imports susceptibility to apoptosis by disrupting the ability of Bcl-xL to block the proapoptotic activity of BH3 domain-only proteins. Conversely, Bcl-xL deamidation is actively suppressed in fibroblasts, and suppression of deamidation is an essential component of their resistance to DNA damage-induced apoptosis. Our results suggest that the regulation of Bcl-xL deamidation has a critical role in the tumor-specific activity of DNA-damaging antineoplastic agents. |
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