自噬活性决定了细胞对致癌性 RAS 的反应。
Autophagic activity dictates the cellular response to oncogenic RAS.
机构信息
Ludwig Institute for Cancer Research Ltd., Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
出版信息
Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):13325-30. doi: 10.1073/pnas.1120193109. Epub 2012 Jul 30.
RAS is frequently mutated in human cancers and has opposing effects on autophagy and tumorigenesis. Identifying determinants of the cellular responses to RAS is therefore vital in cancer research. Here, we show that autophagic activity dictates the cellular response to oncogenic RAS. N-terminal Apoptosis-stimulating of p53 protein 2 (ASPP2) mediates RAS-induced senescence and inhibits autophagy. Oncogenic RAS-expressing ASPP2((Δ3/Δ3)) mouse embryonic fibroblasts that escape senescence express a high level of ATG5/ATG12. Consistent with the notion that autophagy levels control the cellular response to oncogenic RAS, overexpressing ATG5, but not autophagy-deficient ATG5 mutant K130R, bypasses RAS-induced senescence, whereas ATG5 or ATG3 deficiency predisposes to it. Mechanistically, ASPP2 inhibits RAS-induced autophagy by competing with ATG16 to bind ATG5/ATG12 and preventing ATG16/ATG5/ATG12 formation. Hence, ASPP2 modulates oncogenic RAS-induced autophagic activity to dictate the cellular response to RAS: to proliferate or senesce.
RAS 经常在人类癌症中发生突变，对自噬和肿瘤发生有相反的影响。因此，确定细胞对 RAS 反应的决定因素在癌症研究中至关重要。在这里，我们表明自噬活性决定了细胞对致癌 RAS 的反应。p53 蛋白 N 端凋亡刺激因子 2（ASPP2）介导 RAS 诱导的衰老并抑制自噬。逃避衰老的表达致癌 RAS 的 ASPP2((Δ3/Δ3)) 小鼠胚胎成纤维细胞表达高水平的 ATG5/ATG12。与自噬水平控制细胞对致癌 RAS 反应的观点一致，过表达 ATG5，但不是自噬缺陷的 ATG5 突变体 K130R，可绕过 RAS 诱导的衰老，而 ATG5 或 ATG3 缺失则使其易发生衰老。在机制上，ASPP2 通过与 ATG16 竞争结合 ATG5/ATG12 并阻止 ATG16/ATG5/ATG12 的形成来抑制 RAS 诱导的自噬。因此，ASPP2 调节致癌 RAS 诱导的自噬活性，从而决定细胞对 RAS 的反应：增殖或衰老。
Zotero 插件