Laboratorio Nazionale CIB, Area Science Park Padriciano, Trieste, Italy.
Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Nat Cell Biol. 2018 Jan;20(1):28-35. doi: 10.1038/s41556-017-0009-8. Epub 2017 Dec 18.
Tumour-associated p53 missense mutants act as driver oncogenes affecting cancer progression, metastatic potential and drug resistance (gain-of-function) . 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 . 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 . 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.
肿瘤相关的 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（获得功能）。突变 p53 蛋白的稳定是获得功能表现的前提条件；然而，它并不是 p53 突变体的固有特性，而是需要次级事件。此外，突变 p53 蛋白水平在同一肿瘤内甚至常常是异质的，这引发了关于控制局部突变 p53 在某些肿瘤细胞中积累而不在其相邻细胞中积累的机制的问题。通过研究诱导突变 p53 免受泛素介导的蛋白水解保护的细胞途径，我们发现，HDAC6/Hsp90 依赖性突变 p53 积累是由甲羟戊酸途径下游的 RhoA 异戊烯基化以及 RhoA 和肌动蛋白依赖性机械输入（如细胞外环境的硬度）转导所维持的。我们的结果为依赖代谢和机械线索的突变 p53 调节提供了证据。
