Endoplasmic reticulum stress, the unfolded protein response, autophagy, and the integrated regulation of breast cancer cell fate.
Endoplasmic reticulum stress, the unfolded protein response, autophagy, and the integrated regulation of breast cancer cell fate.
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DOI：
10.1158/0008-5472.can-11-3213
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发表时间：
2012-03-15
期刊：
影响因子：
11.2
通讯作者：
Shajahan AN
中科院分区：
文献类型：
--
作者：
Clarke R;Cook KL;Hu R;Facey CO;Tavassoly I;Schwartz JL;Baumann WT;Tyson JJ;Xuan J;Wang Y;Wärri A;Shajahan AN
乳腺癌细胞如何应对内分泌治疗的压力决定了它们是否获得抗性表型或执行细胞死亡途径。一个成功执行的生存信号需要确定是否复制。这些细胞命运决定是如何调控的尚不清楚，但证据表明，决定这些结果的信号是高度整合的。细胞最终命运决定的核心是来自未折叠蛋白反应的信号，它可以在内质网感知压力后被激活。应激反应的持续时间部分是由肌醇需要酶-1 （IRE1； ERN）从热休克蛋白A5 （HSPA5）释放后激活的持续时间介导的。由此产生的信号似乎使用了几个b细胞淋巴瘤-2 （BCL2）家族成员来抑制细胞凋亡和激活自噬。细胞应激引起的代谢变化是该调节系统的关键组成部分，代谢组的进一步适应受到应激反应的影响。在这里，我们描述了未折叠蛋白的反应，自噬和凋亡，以及它们的调节是如何整合的。讨论了整合细胞命运调控和决策执行的信号网络的中心拓扑特征。
How breast cancer cells respond to the stress of endocrine therapies determines whether they acquire a resistant phenotype or execute a cell death pathway. A successfully executed survival signal then requires determination of whether or not to replicate. How these cell fate decisions are regulated is unclear but evidence suggests that the signals determining these outcomes are highly integrated. Central to the final cell fate decision is signaling from the unfolded protein response, which can be activated following the sensing of stress within the endoplasmic reticulum. Duration of the response to stress is partly mediated by the duration of inositol requiring enzyme-1 (IRE1; ERN) activation following its release from heat shock protein A5 (HSPA5). The resulting signaling appears to use several B-cell lymphoma-2 (BCL2) family members to both suppress apoptosis and activate autophagy. Changes in metabolism induced by cellular stress are key components of this regulatory system, and further adaptation of the metabolome is affected in response to stress. Here we describe the unfolded protein response, autophagy and apoptosis, and how their regulation is integrated. Central topological features of the signaling network that integrate cell fate regulation and decision execution are discussed.