PDF(Pubmed)
Abstract：
The tumor suppressor von Hippel-Lindau, pVHL, is a multifaceted protein. One function is to dock to the hypoxia-inducible transcription factor (HIF) and recruit a larger protein complex that destabilizes HIF via ubiquitination, preventing angiogenesis and tumor development. pVHL also binds to the tumor suppressor p53 to activate specific p53 target genes. The oncogene Mdm2 impairs the formation of the p53-pVHL complex and activation of downstream genes by conjugating nedd8 to pVHL. While Mdm2 can impact p53 and pVHL, how pVHL may impact Mdm2 is unclear. Like p53 somatic mutations, point mutations are evident in pVHL that are common in renal clear cell carcinomas (RCC). In patients with RCC, Mdm2 levels are elevated, and we examined whether there was a relationship between Mdm2 and pVHL. TCGA and DepMap analysis revealed that mdm2 gene expression was elevated in RCC with vhl point mutations or copy number loss. In pVHL reconstituted or deleted isogenetically match RCC or MEF cell lines, Mdm2 was decreased in the presence of pVHL. Furthermore, through analysis using genetic and pharmacological approaches, we show that pVHL represses Mdm2 gene expression by blocking the MAPK-Ets signaling pathway and blocks Akt-mediated phosphorylation and stabilization of Mdm2. Mdm2 inhibition results in an increase in the p53-p21 pathway to impede cell growth. This finding shows how pVHL can indirectly impact the function of Mdm2 by regulating signaling pathways to restrict cell growth.
摘要：
肿瘤抑制因子vonHippel-Lindau,pVHL,是一种多方面的蛋白质。一种功能是停靠在缺氧诱导转录因子（HIF）上，并通过泛素化来招募更大的蛋白质复合物，使HIF不稳定。防止血管生成和肿瘤发展。pVHL还与肿瘤抑制因子p53结合以激活特异性p53靶基因。癌基因Mdm2通过将nedd8与pVHL缀合而损害p53-pVHL复合物的形成和下游基因的激活。虽然Mdm2可以影响p53和pVHL，pVHL如何影响Mdm2尚不清楚。像p53体细胞突变，在肾透明细胞癌（RCC）中常见的pVHL中，点突变很明显。在RCC患者中，Mdm2水平升高，我们检查了Mdm2和pVHL之间是否存在关系。TCGA和DepMap分析显示mdm2基因表达在RCC中升高,具有vhl点突变或拷贝数丢失。在pVHL重建或缺失的同源匹配RCC或MEF细胞系中，在pVHL存在下Mdm2降低。此外，通过使用遗传和药理学方法进行分析，我们发现pVHL通过阻断MAPK-Ets信号通路抑制Mdm2基因表达，并阻断Akt介导的Mdm2磷酸化和稳定。Mdm2抑制导致p53-p21途径的增加以阻碍细胞生长。这一发现表明pVHL如何通过调节信号传导途径来限制细胞生长，从而间接影响Mdm2的功能。
