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.

中文翻译：

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pVHL 肿瘤抑制因子抑制激酶信号通路对 Mdm2 基因和蛋白的诱导


肿瘤抑制因子 von Hippel-Lindau (pVHL) 是一种多面蛋白质。其中一项功能是对接缺氧诱导转录因子 (HIF)，并招募更大的蛋白质复合物，通过泛素化破坏 HIF 的稳定性，从而防止血管生成和肿瘤发展。 pVHL 还与肿瘤抑制因子 p53 结合，激活特定的 p53 靶基因。癌基因 Mdm2 通过将 nedd8 与 pVHL 结合来损害 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，但 pVHL 如何影响 Mdm2 尚不清楚。与 p53 体细胞突变一样，点突变在肾透明细胞癌 (RCC) 中常见的 pVHL 中也很明显。在 RCC 患者中，Mdm2 水平升高，我们检查了 Mdm2 和 pVHL 之间是否存在相关性。 TCGA 和 DepMap 分析显示，在伴有 vhl 点突变或拷贝数丢失的 RCC 中，mdm2 基因表达升高。在 pVHL 重建或删除的同基因匹配 RCC 或 MEF 细胞系中，Mdm2 在 pVHL 存在时减少。此外，通过使用遗传和药理学方法的分析，我们表明pVHL通过阻断MAPK-Ets信号通路来抑制Mdm2基因表达，并阻断Akt介导的Mdm2磷酸化和稳定化。 Mdm2 抑制会导致 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限制细胞生长来间接影响 Mdm2 的功能。