Author/Authors :
Benjamin E. Deverman، نويسنده , , Brian L. Cook، نويسنده , , Scott R. Manson، نويسنده , , Robert A. Niederhoff، نويسنده , , Ellen M. Langer، نويسنده , , Ivana Rosov?، نويسنده , , Laura A. Kulans، نويسنده , , Xiaoyun Fu، نويسنده , , Justin S. Weinberg، نويسنده , , Jay W. Heinecke، نويسنده , , Kevin A. Roth، نويسنده , , Steven J. Weintraub، نويسنده ,
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.
