The positive regulation of p53 by the tumor suppressor VHL.
The ubiquitin-mediated degradation of hypoxia-inducible factor-alpha (HIF-alpha) by a von Hippel-Lindau tumor suppressor protein (pVHL) is mechanistically responsible for controlling gene expression due to oxygen availability. Germline mutations in the VHL gene cause dysregulation of HIF and induce an autosomal dominant cancer syndrome referred to as VHL disease. However, it is unclear whether HIF accumulation caused by VHL mutations is sufficient for tumorigenesis. Recently, we found that pVHL directly associates and positively regulates the tumor suppressor p53 by inhibiting Mdm2-mediated ubiquitination, and by subsequently recruiting p53-modifying enzymes. Moreover, VHL-deleted RCC cells showed attenuated apoptosis or abnormal cell-cycle arrest upon DNA damage, but became normal when pVHL was restored. Thus, pVHL appears to play a pivotal role in tumor suppression by participating actively as a component of p53 transactivation complex during DNA damage response.
Roe
Jae-Seok
JS
Department of Biochemistry and Molecular Biology, Cancer Research Institute, Interdisciplinary Program in Genetic Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea.
Youn
Hong-Duk
HD
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D018816:Genes, cdc / Q000502:physiology; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human