Chaperone-mediated autophagy degrades mutant p53
Chaperone-mediated autophagy degrades mutant p53
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DOI：
10.1101/gad.220897.113
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发表时间：
2013-08-01
影响因子：
10.5
通讯作者：
Yuan, Junying
中科院分区：
文献类型：
--
作者：
Vakifahmetoglu-Norberg, Helin;Kim, Minsu;Yuan, Junying
TP53基因是最重要的肿瘤抑制因子之一，编码p53的基因中的错义突变在人类癌症中很常见。已知累积的突变型p53蛋白积极促进肿瘤发展和转移。因此，促进癌细胞中突变型p53蛋白的去除可能具有治疗意义。在这里，我们调查的机制，管理营业额的突变p53在非增殖性肿瘤细胞使用药理学和遗传学的方法相结合。我们发现，通过多种手段抑制巨自噬促进了突变型p53的降解，通过伴侣介导的自噬在溶酶体依赖的方式。此外，由于大自噬抑制导致的突变型p53表达的耗竭使非增殖条件下休眠癌细胞的死亡敏感。两者合计，我们的研究结果描绘了一种新的策略，杀死依赖于突变型p53表达的肿瘤细胞，通过激活分子伴侣介导的自噬和潜在的药理学手段，以减少积累的突变型p53的水平，而不限制突变型p53构象在静止的肿瘤细胞。
Missense mutations in the gene TP53, which encodes p53, one of the most important tumor suppressors, are common in human cancers. Accumulated mutant p53 proteins are known to actively contribute to tumor development and metastasis. Thus, promoting the removal of mutant p53 proteins in cancer cells may have therapeutic significance. Here we investigated the mechanisms that govern the turnover of mutant p53 in nonproliferating tumor cells using a combination of pharmacological and genetic approaches. We show that suppression of macroautophagy by multiple means promotes the degradation of mutant p53 through chaperone-mediated autophagy in a lysosome-dependent fashion. In addition, depletion of mutant p53 expression due to macroautophagy inhibition sensitizes the death of dormant cancer cells under nonproliferating conditions. Taken together, our results delineate a novel strategy for killing tumor cells that depend on mutant p53 expression by the activation of chaperone-mediated autophagy and potential pharmacological means to reduce the levels of accumulated mutant p53 without the restriction of mutant p53 conformation in quiescent tumor cells.