2017
DOI: 10.1038/s41556-017-0009-8
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Mechanical cues control mutant p53 stability through a mevalonate–RhoA axis

Abstract: 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 accumulati… Show more

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Cited by 112 publications
(140 citation statements)
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“…Mechanistically, statins inhibit the mevalonate-5-phosphate pathway and induce E3 Ubiquitin-Protein Ligase CHIP -mediated degradation of mutant p53, by impairing the interaction of mutant p53 with DNAJA1 (DnaJ Heat Shock Protein Family Member A1), an Hsp40 isoform, similarly to Hsp90s involved in mutant p53 protection [131]. As mentioned above, statins also degrade mutant p53 proteins by interfering with the mevalonate-geranylgeranyl-pyrophosphate-RhoA mechanosignaling pathway, which controls Hsp90-dependent p53 mutant stabilization [118]. Overall, bi-directional interactions between mutant p53 and the mevalonic pathway could be a promising therapeutic target.…”
Section: Therapies To Induce Mutant P53 Degradationmentioning
confidence: 99%
See 1 more Smart Citation
“…Mechanistically, statins inhibit the mevalonate-5-phosphate pathway and induce E3 Ubiquitin-Protein Ligase CHIP -mediated degradation of mutant p53, by impairing the interaction of mutant p53 with DNAJA1 (DnaJ Heat Shock Protein Family Member A1), an Hsp40 isoform, similarly to Hsp90s involved in mutant p53 protection [131]. As mentioned above, statins also degrade mutant p53 proteins by interfering with the mevalonate-geranylgeranyl-pyrophosphate-RhoA mechanosignaling pathway, which controls Hsp90-dependent p53 mutant stabilization [118]. Overall, bi-directional interactions between mutant p53 and the mevalonic pathway could be a promising therapeutic target.…”
Section: Therapies To Induce Mutant P53 Degradationmentioning
confidence: 99%
“…The RhoA mediated mechanosignaling in turn requires the mevalonate pathway. Indeed, in addition to cholesterol biosynthesis, this pathway also provides geranylgeranyl pyrophosphate (GGPP) that is required for cellular membrane anchoring, and activation of RhoA (Figure 3) [118]. Thus, p53 mutants promote the mevalonate pathway [103], whose activation in turn induces the accumulation of mutant p53 protein in cancer cells.…”
Section: Role Of Mutant P53 Gain Of Function In Metabolism and Hypoxiamentioning
confidence: 99%
“…The mixture of siRNA and transfection reagent was added to the cell culture plate dropwise and cells were incubated for 72 h prior to measurement. We used the following siRNA sequences for RhoA and scrambled control (11,26): siRhoA-#1: 5'-AUGGAAAGCAGGUAGAGUU-3', siRhoA-#2: 5'-GAAAGACAUGCUUGCUCAU-3', siControl: 5′-CAGUCAGGAGGAUCCAAAGTG-3′.…”
Section: Cell Lines and Reagentsmentioning
confidence: 99%
“…Mechanical cues, such as increased matrix stiffness in tumors, cause cancer cells to increase their stiffness and force production (8)(9)(10). While various soluble and mechanical cues are known to regulate cancer cell mechanotype (11,12), our knowledge of the shared molecular mediators that regulate cellular mechanotype and functional behaviors to drive metastasis is still emerging.…”
Section: Introductionmentioning
confidence: 99%
“…Mutant p53 can upregulate expression of mevalonate pathway genes, possibly through interaction with SREBP-2, the key transcriptional factor of many sterol biosynthesis genes, and this determines a susceptibility of the mevalonic pathway to the p53 status in the cancer cells [74]. One of the important outputs of the mevalonate pathway is RhoA geranylgeranylation which can lead to stabilized mutant p53 [101]. Interestingly, statins also destabilize mutant p53, although the mechanism appears to involve counteracting DNAJA1 interaction with mutant p53 [102].…”
Section: The Case Of Clear Cell Renal Cell Carcinoma and Bap1mentioning
confidence: 99%