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TRIM8 modulates p53 activity to dictate cell cycle arrest

机译：TRIM8调节p53活性以指示细胞周期停滞

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摘要

p53 is a central hub in controlling cell proliferation. To maintain genome integrity in response to cellular stress, p53 directly regulates the transcription of genes involved in cell cycle arrest, DNA repair, apoptosis and/or senescence. An array of post-translational modifications and protein-protein interactions modulates its stability and activities in order to avoid malignant transformation. However, to date, it is still not clear how cells decide their own fate in response to different types of stress. Here we describe that the human TRIM8 protein, a member of the TRIM family, is a new modulator of the p53-mediated tumor suppression mechanism. We show that under stress conditions, such as UV exposure, p53 induced the expression of TRIM8, which, in turn, stabilized p53, leading to cell cycle arrest and reduction of cell proliferation through enhancement of CDKN1A (p21) and GADD45 expression. TRIM8 silencing reduced the capacity of p53 to activate genes involved in cell cycle arrest and DNA repair in response to cellular stress. Concurrently, TRIM8 overexpression induced the degradation of the MDM2 protein, the principal regulator of p53 stability. Co-immunoprecipitation experiments showed that TRIM8 physically interacted with p53, impairing its interaction with MDM2. Altogether, our results reveal a previously unknown regulatory pathway controlling p53 activity and suggest TRIM8 as a novel therapeutic target to enhance p53 tumor suppressor activity.
机译：p53是控制细胞增殖的中心枢纽。为了维持响应细胞压力的基因组完整性，p53直接调节参与细胞周期停滞，DNA修复，细胞凋亡和/或衰老的基因的转录。翻译后修饰和蛋白质-蛋白质相互作用的一系列调节其稳定性和活性，以避免恶性转化。然而，迄今为止，还不清楚细胞如何响应不同类型的压力来决定自己的命运。在这里，我们描述了人类TRIM8蛋白（TRIM家族的成员）是p53介导的肿瘤抑制机制的新调节剂。我们表明，在应激条件下，例如紫外线暴露下，p53诱导了TRIM8的表达，而TRIM8则稳定了p53，从而导致细胞周期停滞并通过增强CDKN1A（p21）和GADD45的表达而减少了细胞的增殖。 TRIM8沉默降低了p53激活响应细胞应激而参与细胞周期停滞和DNA修复的基因的能力。同时，TRIM8过表达诱导了MDM2蛋白的降解，MDM2蛋白是p53稳定性的主要调节因子。免疫共沉淀实验表明，TRIM8与p53发生物理相互作用，从而削弱了其与MDM2的相互作用。总而言之，我们的结果揭示了控制p53活性的未知途径，并暗示TRIM8是增强p53肿瘤抑制活性的新型治疗靶标。

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