Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity.
Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity.
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DOI：
10.1038/s41467-021-24064-1
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发表时间：
2021-06-29
影响因子：
16.6
通讯作者：
Schulz-Heddergott R
中科院分区：
文献类型：
--
作者：
Isermann T;Şener ÖÇ;Stender A;Klemke L;Winkler N;Neesse A;Li J;Wegwitz F;Moll UM;Schulz-Heddergott R
绝大多数具有p53突变的人类肿瘤经历剩余野生型p53等位基因的丢失（杂合性丢失，p53 LOH）。p53 LOH在促进肿瘤进展中具有分水岭意义。然而，p53 LOH的驱动力知之甚少。在这里，我们确定了抑制性WTP 53-HSF 1轴作为p53 LOH的一个驱动因素。我们发现p53 R248 Q/+小鼠AOM/DSS化学诱导的结直肠肿瘤（CRC）中的WTP 53等位基因保留了部分活性并抑制热休克因子1（HSF 1），HSF 1是蛋白毒性应激反应（HSR）的主要调节因子，在癌症中普遍激活。HSR对于稳定包括mutp 53在内的致癌蛋白至关重要。保留WTp 53的CRC肿瘤，肿瘤衍生的类器官和人CRC细胞都抑制了肿瘤促进HSF 1程序。从机制上讲，保留的WTP 53激活CDKN 1A/p21，导致细胞周期抑制和E2 F靶点MLK 3的抑制。MLK 3将细胞周期与MAPK应激途径联系起来以激活HSR反应。在p53 R248 Q/+肿瘤中，组成性应激引起的WTP 53活化抑制MLK 3，从而减弱肿瘤存活所必需的MAPK-HSF 1应答。这产生了p53 LOH的选择压力，其消除了抑制性WTp 53-MAPK-HSF 1轴并释放了促肿瘤HSF 1功能，诱导mutp 53稳定化，从而使侵袭成为可能。大多数突变型p53杂合肿瘤经历剩余野生型（WT）p53等位基因的丢失，这导致突变型p53蛋白的稳定。在这里，作者在本地结直肠癌模型中显示，WT p53等位基因保留部分活性并抑制热休克因子1（HSF 1）-伴侣轴，以防止突变型p53稳定和突变型p53功能获得活性，从而为p53杂合性丧失产生选择性压力。
The vast majority of human tumors with p53 mutations undergo loss of the remaining wildtype p53 allele (loss-of-heterozygosity, p53LOH). p53LOH has watershed significance in promoting tumor progression. However, driving forces for p53LOH are poorly understood. Here we identify the repressive WTp53–HSF1 axis as one driver of p53LOH. We find that the WTp53 allele in AOM/DSS chemically-induced colorectal tumors (CRC) of p53R248Q/+ mice retains partial activity and represses heat-shock factor 1 (HSF1), the master regulator of the proteotoxic stress response (HSR) that is ubiquitously activated in cancer. HSR is critical for stabilizing oncogenic proteins including mutp53. WTp53-retaining CRC tumors, tumor-derived organoids and human CRC cells all suppress the tumor-promoting HSF1 program. Mechanistically, retained WTp53 activates CDKN1A/p21, causing cell cycle inhibition and suppression of E2F target MLK3. MLK3 links cell cycle with the MAPK stress pathway to activate the HSR response. In p53R248Q/+ tumors WTp53 activation by constitutive stress represses MLK3, thereby weakening the MAPK-HSF1 response necessary for tumor survival. This creates selection pressure for p53LOH which eliminates the repressive WTp53-MAPK-HSF1 axis and unleashes tumor-promoting HSF1 functions, inducing mutp53 stabilization enabling invasion. Most mutant p53 heterozygous tumours undergo loss of the remaining wildtype (WT) p53 allele which leads to stabilization of the mutant p53 protein. Here, the authors show in an autochthonous colorectal cancer model that the WT p53 allele retains partial activity and suppresses the heat shock factor 1 (HSF1)- chaperone axis to prevent mutant p53 stabilisation and mutant p53 gain-of-function activities, thereby creating selective pressure for p53 loss-of-heterozygosity.
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影响因子：
--
作者：
Iyer SV;Parrales A;Begani P;Narkar A;Adhikari AS;Martinez LA;Iwakuma T
通讯作者：
Iwakuma T
影响因子：
64.5
作者：
Dai, Chengkai;Whitesell, Luke;Lindquist, Susan
通讯作者：
Lindquist, Susan
影响因子：
9
作者：
Alexandrova, Evguenia M.;Mirza, Safia A.;Moll, Ute M.
通讯作者：
Moll, Ute M.
影响因子：
6
作者：
Hasselluhn, Marie C.;Klein, Lukas;Neesse, Albrecht
通讯作者：
Neesse, Albrecht
DOI：
10.1038/nrm.2017.73
发表时间：
2018-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Gomez-Pastor R;Burchfiel ET;Thiele DJ
通讯作者：
Thiele DJ