von Hippel-Lindau (VHL) disease is a rare autosomal dominant cancer syndrome. Although hypoxia-inducible factor-α (HIFα) 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.
Bibliographical noteFunding Information:
We thank Dr. B. Vogelstein, Dr. T. Taniguchi, Dr. G. Lozano, Dr. C.W. Lee, and Dr. J.H. Choe for invaluable materials. We also thank Dr. J.O. Liu (The Johns Hopkins School of Medicine) for critical reading of this manuscript, and anonymous reviewers who gave us invaluable comments to upgrade this manuscript. This work was supported by a grant of the National R&D Program for Cancer Control, Ministry of Health & Welfare, Korea (0420010-2) (to H.-D.Y.). J.-S.R. was supported by the Seoul Science Fellowship.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology