HMGA2 promotes intestinal tumorigenesis by facilitating MDM2-mediated ubiquitination and degradation of p53
HMGA2 promotes intestinal tumorigenesis by facilitating MDM2-mediated ubiquitination and degradation of p53
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HMGA2 通过促进 MDM2 介导的 p53 泛素化和降解来促进肠道肿瘤发生
DOI：
10.1002/path.5164
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发表时间：
2018-12-01
影响因子：
7.3
通讯作者：
Lai, Maode
中科院分区：
文献类型：
--
作者：
Wang, Yuhong;Hu, Lin;Lai, Maode
高迁移率族A2(HMGA2)是一种结构型转录因子，通过调控靶基因的转录促进结直肠癌的侵袭性。P53的降解是由小鼠双分钟2(MDM2)以蛋白酶体依赖的方式介导的。在此，我们报道了HMGA2促进细胞周期进展和抑制体外培养的结直肠癌细胞的凋亡。我们还建立了肠上皮细胞特异性HMGA2基因敲入(KI)小鼠模型。提示HMGA2KI在体内促进了化学致癌物诱导的肠道肿瘤的发生。在研究其潜在的分子机制时，我们发现HMGA2与P53形成了蛋白质复合体。P53的四聚结构域(294-393位氨基酸)和HMGA2的3个AT-钩区(1-83位氨基酸)直接相互作用。我们还发现HMGA2直接与MDM2结合，MDM2的中心酸性和锌指结构域(氨基酸111-360)需要与HMGA2相互作用。此外，我们的结果表明，HMGA2促进了MDM2介导的p53泛素化和降解。有趣的是，HMGA2在HMGA2Ki小鼠中的过度表达导致泛素化的p53积累增加。此外，在两个大型结直肠癌队列中，研究表明，在p53阴性的结直肠癌患者亚组中，HMGA2的高表达预示着不良结局。综上所述，我们的数据首次建立了一种新的机制，通过HMGA2与P53和MDM2一起促进CRC的进展。版权所有(C)2018年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
High mobility group A2 (HMGA2) is an architectural transcription factor that promotes human colorectal cancer (CRC) aggressiveness by modulating the transcription of target genes. The degradation of p53 is mediated by murine double minute 2 (MDM2) in a proteasome-dependent manner. Here we report that HMGA2 promotes cell cycle progression and inhibits apoptosis in CRC cells in vitro. We also developed an intestinal epithelial cell-specific Hmga2 knock-in (KI) mouse model. It revealed that the Hmga2 KI promoted chemical carcinogen-induced tumorigenesis in the intestine in vivo. In studying the underlying molecular mechanism, we found that HMGA2 formed a protein complex with p53. The tetramerization domain of p53 (amino acids 294-393) and the three AT-hook domains (amino acids 1-83) of HMGA2 were responsible for their direct interaction. We also found that HMGA2 directly bound to MDM2 and the central acidic and zinc finger domains of MDM2 (amino acids 111-360) were required for interaction with HMGA2. Furthermore, our results indicated that HMGA2 promoted MDM2-mediated p53 ubiquitination and degradation. Interestingly, Hmga2 overexpression in Hmga2 KI mice resulted in an increase in the accumulation of ubiquitinated p53. In addition, in two large CRC cohorts, it was demonstrated that high HMGA2 expression was predictive of an adverse outcome in the p53-negative subgroup of CRC patients. In summary, our data have established for the first time a novel mechanism by which HMGA2 functions with p53 and MDM2 to promote CRC progression. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.