Bcl-XL deamidation is a critical switch in the regulation of the response to DNA damage

被引：202

作者：

Deverman, BE

Cook, BL

Manson, SR

Niederhoff, RA

Langer, EM

Rosová, I

Kulans, LA

Fu, XY

Weinberg, JS

Heinecke, JW

Roth, KA

Weintraub, SJ

机构：

[1] Washington Univ, Sch Med, Dept Cell Biol & Physiol, Div Urol, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA

[3] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO 63110 USA

[4] Washington Univ, Sch Med, Dept Mol Biol & Pharmacol, St Louis, MO 63110 USA

[5] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA

[6] Washington Univ, Sch Med, Dept Immunol, St Louis, MO 63110 USA

来源：

CELL | 2002年 / 111卷 / 01期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1016/S0092-8674(02)00972-8

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-X-L, and we demonstrate that deamidation of these asparagines imports susceptibility to apoptosis by disrupting the ability of BcI-X-L to block the proapoptotic activity of BH3 domain-only proteins. Conversely, Bcl-X-L 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-X-L deamidation has a critical role in the tumor-specific activity of DNA-damaging antineoplastic agents.

引用

页码：51 / 62

页数：12

共 47 条

[1] DEFICIENCY OF RETINOBLASTOMA PROTEIN LEADS TO INAPPROPRIATE S-PHASE ENTRY, ACTIVATION OF E2F-RESPONSIVE GENES, AND APOPTOSIS [J].