Tumour-associated p53 missense mutants act as driver oncogenes affecting cancer progression, metastatic potential and drug resistance (gain-of-function) ¹ . Mutant p53 protein stabilization is a prerequisite for gain-of-function manifestation; however, it does not represent an intrinsic property of p53 mutants, but rather requires secondary events ² . Moreover, mutant p53 protein levels are often heterogeneous even within the same tumour, raising questions on the mechanisms that control local mutant p53 accumulation in some tumour cells but not in their neighbours ^2,3 . By investigating the cellular pathways that induce protection of mutant p53 from ubiquitin-mediated proteolysis, we found that HDAC6/Hsp90-dependent mutant p53 accumulation is sustained by RhoA geranylgeranylation downstream of the mevalonate pathway, as well as by RhoA- and actin-dependent transduction of mechanical inputs, such as the stiffness of the extracellular environment. Our results provide evidence for an unpredicted layer of mutant p53 regulation that relies on metabolic and mechanical cues.

中文翻译：

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机械线索通过甲羟戊酸-RhoA 轴控制突变 p53 的稳定性。

肿瘤相关 p53 错义突变体作为驱动癌基因影响癌症进展、转移潜能和耐药性（功能获得）¹。突变 p53 蛋白稳定化是功能获得表现的先决条件；然而，它并不代表 p53 突变体的内在特性，而是需要次要事件²。此外，即使在同一肿瘤内，突变 p53 蛋白水平通常也是异质的，这引发了对控制某些肿瘤细胞中局部突变 p53 积累而不是其邻居细胞中的局部突变 p53 积累的机制的质疑^2,3. 通过研究诱导保护突变体 p53 免受泛素介导的蛋白水解的细胞途径，我们发现 HDAC6/Hsp90 依赖性突变体 p53 的积累是由甲羟戊酸途径下游的 RhoA 香叶基香叶基化以及 RhoA 和肌动蛋白依赖性转导维持的机械输入，例如细胞外环境的刚度。我们的研究结果为依赖于代谢和机械信号的突变 p53 调控层提供了证据。