TY - JOUR
T1 - Bcl-xL deamidation is a critical switch in the regulation of the response to DNA damage
AU - Deverman, Benjamin E.
AU - Cook, Brian L.
AU - Manson, Scott R.
AU - Niederhoff, Robert A.
AU - Langer, Ellen M.
AU - Rosová, Ivana
AU - Kulans, Laura A.
AU - Fu, Xiaoyun
AU - Weinberg, Justin S.
AU - Heinecke, Jay W.
AU - Roth, Kevin A.
AU - Weintraub, Steven J.
PY - 2002/10/4
Y1 - 2002/10/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=18644376568&partnerID=8YFLogxK
U2 - 10.1016/S0092-8674(02)00972-8
DO - 10.1016/S0092-8674(02)00972-8
M3 - Article
C2 - 12372300
AN - SCOPUS:18644376568
VL - 111
SP - 51
EP - 62
JO - Cell
JF - Cell
SN - 0092-8674
IS - 1
ER -