Regulation of p53 oligomerization by Ras superfamily protein RBEL1A.
Regulation of p53 oligomerization by Ras superfamily protein RBEL1A.
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DOI：
10.18632/genesandcancer.71
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Huang Y
中科院分区：
文献类型：
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作者：
Lui K;Sheikh MS;Huang Y
我们之前的研究表明，RBEL1A在多种人类恶性肿瘤中过表达，RNAi对其的消耗导致肿瘤细胞严重的生长抑制。我们还发现RBEL1A直接与p53相互作用，这种相互作用发生在p53的寡聚结构域。然而，这种相互作用对p53寡聚化和功能的影响仍有待研究。在这里，我们报道了RBEL1A和p53的相互作用在非应激细胞和暴露于DNA损伤的细胞中抑制p53寡聚物的形成。此外，纯化的RBEL1A在体外阻断了315-360残基对应的重组p53的寡聚化。RBEL1A还显著降低了细胞中外源表达的p53 c端区域（残基301-393）的寡聚化。RBEL1A的过表达（如在人类肿瘤中所见）也抑制了内源性p53的寡聚化。我们的研究结果还表明，RBEL1A残基1-235处的GTPase结构域足以阻止p53寡聚化。此外，内源性RBEL1A的沉默显著增强了紫外线辐射介导的DNA损伤后p53寡聚物的形成，RBEL1A的敲低也增强了p53靶基因的表达。总之，我们的研究为p53的调控和RBEL1A在人类恶性肿瘤中的致癌作用提供了重要的新分子见解。RBEL1A在人类肿瘤中的表达升高可以通过抑制p53的四聚体化来负向调节p53。
Our previous studies showed that RBEL1A overexpressed in multiple human malignancies and its depletion by RNAi caused severe growth inhibition in tumor cells. We also showed that RBEL1A directly interacted with p53 and such interactions occurred at the oligomeric domain of p53. However, the effect of such interactions on p53 oligomerization and function remained to be investigated. Here, we report that the interaction of RBEL1A and p53 suppressed p53 oligomer formation in unstressed cells and in cells exposed to DNA damage. Furthermore, purified RBEL1A blocked the oligomerization of recombinant p53 corresponding to residues 315-360 in vitro. RBEL1A also significantly reduced the oligomerization of the exogenously expressed C-terminal region (residues 301-393) of p53 in cells. Overexpression of RBEL1A (as seen in human tumors), also suppressed oligomerization by endogenous p53. Our results also showed that GTPase domain of RBEL1A at residues 1-235 was sufficient to block p53 oligomerization. Furthermore, silencing of endogenous RBEL1A significantly enhanced the formation of p53 oligomeric complex following ultraviolet radiation-mediated DNA damage and RBEL1A knockdown also enhanced expression of p53 target genes. Taken together, our studies provide important new molecular insights into the regulation of p53 and the oncogenic role of RBEL1A in the context to human malignancy. Elevated RBEL1A expression in human tumors could negatively regulate p53 by inhibiting its tetramerization.