The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, Texas.
Department of Genetics, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas.
Cancer Discov. 2023 May 4;13(5):1230-1249. doi: 10.1158/2159-8290.CD-22-0872.
Cancer-related alterations of the p53 tetramerization domain (TD) abrogate wild-type (WT) p53 function. They result in a protein that preferentially forms monomers or dimers, which are also normal p53 states under basal cellular conditions. However, their physiologic relevance is not well understood. We have established in vivo models for monomeric and dimeric p53, which model Li-Fraumeni syndrome patients with germline p53 TD alterations. p53 monomers are inactive forms of the protein. Unexpectedly, p53 dimers conferred some tumor suppression that is not mediated by canonical WT p53 activities. p53 dimers upregulate the PPAR pathway. These activities are associated with lower prevalence of thymic lymphomas and increased CD8+ T-cell differentiation. Lymphomas derived from dimeric p53 mice show cooperating alterations in the PPAR pathway, further implicating a role for these activities in tumor suppression. Our data reveal novel functions for p53 dimers and support the exploration of PPAR agonists as therapies.
New mouse models with TP53R342P (monomer) or TP53A347D (dimer) mutations mimic Li-Fraumeni syndrome. Although p53 monomers lack function, p53 dimers conferred noncanonical tumor-suppressive activities. We describe novel activities for p53 dimers facilitated by PPARs and propose these are "basal" p53 activities. See related commentary by Stieg et al., p. 1046. See related article by Choe et al., p. 1250. This article is highlighted in the In This Issue feature, p. 1027.
p53 四聚体结构域（TD）的癌症相关改变会使野生型（WT）p53 丧失功能。这些改变会导致 p53 优先形成单体或二聚体，而在基础细胞条件下，这些状态也是正常的 p53 状态。然而，它们的生理相关性尚不清楚。我们已经建立了单体和二聚体 p53 的体内模型，这些模型模拟了具有种系 p53 TD 改变的 Li-Fraumeni 综合征患者。p53 单体是该蛋白的无活性形式。出乎意料的是，p53 二聚体赋予了一些肿瘤抑制作用，而这种作用不是由经典的 WT p53 活性介导的。p53 二聚体上调了 PPAR 通路。这些活性与胸腺淋巴瘤的低发生率和 CD8+T 细胞分化的增加有关。源自二聚体 p53 小鼠的淋巴瘤显示出 PPAR 通路的协同改变，进一步表明这些活性在肿瘤抑制中起作用。我们的数据揭示了 p53 二聚体的新功能，并支持探索 PPAR 激动剂作为治疗方法。
具有 TP53R342P（单体）或 TP53A347D（二聚体）突变的新型小鼠模型模拟了 Li-Fraumeni 综合征。尽管 p53 单体缺乏功能，但 p53 二聚体赋予了非经典的肿瘤抑制活性。我们描述了 p53 二聚体通过 PPARs 实现的新活性，并提出这些是“基础”p53 活性。请参阅 Stieg 等人在本期特色文章中的相关评论，第 1046 页。请参阅 Choe 等人在本期杂志中的相关文章，第 1250 页。本文在本期特色文章中重点介绍，第 1027 页。
