Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46022.
Indiana University School of Medicine, Indianapolis, IN 46022.
Proc Natl Acad Sci U S A. 2024 Jul 30;121(31):e2400935121. doi: 10.1073/pnas.2400935121. Epub 2024 Jul 24.
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 gene expression was elevated in RCC with 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.
抑癌基因 von Hippel-Lindau（VHL）蛋白是一种多功能蛋白。其功能之一是与缺氧诱导转录因子（HIF）结合，并募集一个更大的蛋白质复合物，通过泛素化使 HIF 不稳定，从而阻止血管生成和肿瘤发展。VHL 还与肿瘤抑制因子 p53 结合，通过激活特定的 p53 靶基因来激活 p53。癌基因 Mdm2 通过将 nedd8 缀合到 VHL 上来破坏 p53-VHL 复合物的形成和下游基因的激活。虽然 Mdm2 可以影响 p53 和 pVHL，但 pVHL 如何影响 Mdm2 尚不清楚。与 p53 体细胞突变一样，pVHL 中的点突变在肾透明细胞癌（RCC）中很常见。在 RCC 患者中，Mdm2 水平升高，我们研究了 Mdm2 与 pVHL 之间是否存在关系。TCGA 和 DepMap 分析显示，在具有 pVHL 点突变或拷贝数缺失的 RCC 中，基因表达升高。在 pVHL 重建或同基因匹配的 RCC 或 MEF 细胞系中，存在 pVHL 时 Mdm2 减少。此外，通过遗传和药理学方法分析，我们表明 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 通路增加，从而阻碍细胞生长。这一发现表明，pVHL 如何通过调节信号通路来间接影响 Mdm2 的功能，从而限制细胞生长。
