Bcl-xL脱酰胺作用是DNA损伤反应调控中的一个关键开关。

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

作者信息

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

机构信息

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.

出版信息

Cell. 2002 Oct 4;111(1):51-62. doi: 10.1016/s0092-8674(02)00972-8.

DOI:10.1016/s0092-8674(02)00972-8

PMID:12372300

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.

摘要

DNA损伤性抗肿瘤药物的治疗价值取决于它们诱导肿瘤细胞凋亡同时使大多数正常组织免受损伤的能力。在此，我们表明在几种不同类型的肿瘤细胞中，对这些药物凋亡反应的一个组成部分是Bcl-xL无结构环中两个天冬酰胺的脱酰胺作用，并且我们证明这些天冬酰胺的脱酰胺作用通过破坏Bcl-xL阻断仅含BH3结构域蛋白的促凋亡活性的能力而使细胞易于发生凋亡。相反，成纤维细胞中Bcl-xL脱酰胺作用受到积极抑制，并且脱酰胺作用的抑制是它们对DNA损伤诱导的凋亡产生抗性的一个重要组成部分。我们的结果表明，Bcl-xL脱酰胺作用的调控在DNA损伤性抗肿瘤药物的肿瘤特异性活性中起关键作用。