DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway.
DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway.
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DOI：
10.1038/ncb3427
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发表时间：
2016-11
影响因子：
21.3
通讯作者：
Iwakuma T
中科院分区：
文献类型：
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作者：
Parrales A;Ranjan A;Iyer SV;Padhye S;Weir SJ;Roy A;Iwakuma T
肿瘤中突变型p53 （mutp53）的稳定极大地促进了恶性进展。然而，对破坏mutp53的潜在机制和治疗方法知之甚少。在这里，通过高通量筛选，我们确定了他汀类降胆固醇药物作为构象或错误折叠p53突变体的降解诱导剂，对野生型p53 （wtp53）和DNA接触突变体的影响最小。他汀类药物优先抑制表达mutp53的癌细胞生长。通过他汀类药物或甲羟戊酸激酶敲低特异性地减少甲羟戊酸-5-磷酸，可诱导CHIP泛素连接酶介导的核输出、泛素化和通过损害mutp53与Hsp40家族成员DNAJA1的相互作用来降解mutp53。敲低DNAJA1也可诱导chip介导的mutp53降解，而其过表达可拮抗他汀类药物诱导的mutp53降解。我们的研究揭示了DNAJA1控制错误折叠mutp53的命运，提供了通过甲羟戊酸途径- DNAJA1轴消耗mutp53的潜在策略，并强调了p53状态在影响他汀类药物治疗癌症疗效中的重要性。
Stabilization of mutant p53 (mutp53) in tumours greatly contributes to malignant progression. However, little is known about the underlying mechanisms and therapeutic approaches to destabilize mutp53. Here, through high-throughput screening we identify statins, cholesterol-lowering drugs, as degradation inducers for conformational or misfolded p53 mutants with minimal effects on wild-type p53 (wtp53) and DNA contact mutants. Statins preferentially suppress mutp53-expressing cancer cell growth. Specific reduction of mevalonate-5-phosphate by statins or mevalonate kinase knockdown induces CHIP ubiquitin ligase-mediated nuclear export, ubiquitylation, and degradation of mutp53 by impairing interaction of mutp53 with DNAJA1, a Hsp40 family member. Knockdown of DNAJA1 also induces CHIP-mediated mutp53 degradation, while its overexpression antagonizes statin-induced mutp53 degradation. Our study reveals that DNAJA1 controls the fate of misfolded mutp53, provides insights into potential strategies to deplete mutp53 through the mevalonate pathway–DNAJA1 axis, and highlights the significance of p53 status in impacting statins’ efficacy on cancer therapy.