p53 stabilization and transactivation by a von Hippel-Lindau protein.
von Hippel-Lindau (VHL) disease is a rare autosomal dominant cancer syndrome. Although hypoxia-inducible factor-alpha (HIFalpha) is a well-documented substrate of von Hippel-Lindau tumor suppressor protein (pVHL), it remains unclear whether the dysregulation of HIF is sufficient to account for de novo tumorigenesis in VHL-deleted cells. Here we found that pVHL directly associates with and stabilizes p53 by suppressing Mdm2-mediated ubiquitination and nuclear export of p53. Moreover, upon genotoxic stress, pVHL invoked an interaction between p53 and p300 and the acetylation of p53, which ultimately led to an increase in p53 transcriptional activity and p53-mediated cell cycle arrest and apoptosis. These results suggest that the tumor suppressor pVHL has an unexpected function to upregulate the tumor suppressor p53.
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 110-799, Republic of Korea.
Kim
Hyungsoo
H
Lee
Soon-Min
SM
Kim
Sung-Tae
ST
Cho
Eun-Jung
EJ
Youn
Hong-Duk
HD