Nuclear inclusion bodies of mutant and wild-type p53 in cancer: a hallmark of p53 inactivation and proteostasis remodelling by p53 aggregation
Nuclear inclusion bodies of mutant and wild-type p53 in cancer: a hallmark of p53 inactivation and proteostasis remodelling by p53 aggregation
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DOI：
10.1002/path.4872
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发表时间：
2017-05-01
影响因子：
7.3
通讯作者：
Rousseau, Frederic
中科院分区：
文献类型：
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作者：
De Smet, Frederik;Rubio, Mirian Saiz;Rousseau, Frederic
尽管在癌细胞系和肿瘤组织中已经观察到p53蛋白聚集，但它们对癌症的影响在很大程度上仍然未知。在这里，我们在肿瘤活检中广泛筛选p53聚集表型，并确定转录失活突变型或野生型p53的核包络体（nIBs）是六种不同癌症类型中最常见的聚集样表型。p53阳性nib与核聚集标记共染色，并共享神经退行性疾病中常见的nib的分子特征。在细胞培养中，肿瘤相关应激是p53聚集和nIB形成的强诱导剂。这在突变型p53中最为突出，但在野生型p53细胞系中也可以观察到，nIB的形成与p53转录活性的丧失相关。重要的是，蛋白质聚集还通过诱导过度激活的致癌热休克反应（肿瘤通常对热休克反应上瘾），以及通过使蛋白酶体降解系统过载（在结构不稳定的突变型p53中最明显），促进了肿瘤细胞中蛋白酶平衡网络的失调。具有p53阳性nib的肿瘤患者的临床预后较差，与p53表达缺失的患者相似，肿瘤活检显示与p53阳性nib相关的差异蛋白抑制表达谱。因此，p53阳性nib强调了肿瘤的恶性状态，这是由以下两种因素相互作用造成的：(1)p53通过突变和/或聚集的功能失活，以及(2)微环境应激，这两种组合催化了蛋白酶抑制失调。这项研究强调了癌症和神经变性之间一些意想不到的临床、生物学和治疗上未探索的相似之处。版权所有2016年英国和爱尔兰病理学会。约翰·威利父子有限公司出版。
Although p53 protein aggregates have been observed in cancer cell lines and tumour tissue, their impact in cancer remains largely unknown. Here, we extensively screened for p53 aggregation phenotypes in tumour biopsies, and identified nuclear inclusion bodies (nIBs) of transcriptionally inactive mutant or wild-type p53 as the most frequent aggregation-like phenotype across six different cancer types. p53-positive nIBs co-stained with nuclear aggregation markers, and shared molecular hallmarks of nIBs commonly found in neurodegenerative disorders. In cell culture, tumour-associated stress was a strong inducer of p53 aggregation and nIB formation. This was most prominent for mutant p53, but could also be observed in wild-type p53 cell lines, for which nIB formation correlated with the loss of p53's transcriptional activity. Importantly, protein aggregation also fuelled the dysregulation of the proteostasis network in the tumour cell by inducing a hyperactivated, oncogenic heat-shock response, to which tumours are commonly addicted, and by overloading the proteasomal degradation system, an observation that was most pronounced for structurally destabilized mutant p53. Patients showing tumours with p53-positive nIBs suffered from a poor clinical outcome, similar to those with loss of p53 expression, and tumour biopsies showed a differential proteostatic expression profile associated with p53-positive nIBs. p53-positive nIBs therefore highlight a malignant state of the tumour that results from the interplay between (1) the functional inactivation of p53 through mutation and/or aggregation, and (2) microenvironmental stress, a combination that catalyses proteostatic dysregulation. This study highlights several unexpected clinical, biological and therapeutically unexplored parallels between cancer and neurodegeneration. Copyright (C) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.