Abstract

Revised Abstract: Renal cancer is a devastating malignancy that is highly resistant to medical therapy. The VHL tumor suppressor is mutated in most adult renal cancers. Yet, the mechanism of VHL tumor suppression is not known. Using a directed approach to find VHL-interacting proteins important in renal cancer, our laboratory has identified Jade-1 (gene for Apoptosis and Differentiation in Epithelia) as a particularly strong VHL interactor. Jade-1, a novel,kidney-enriched, PEST and plant homeodomain protein, is a member of a new protein family. VHL stabilizes Jade-1 protein, which is a new VHL function. Moreover, we have now shown that Jade-1 stabilization is VHL mutation-dependent, with non-renal cancer-causing VHL missense mutations able to stabilize Jade-1 like wild-type VHL. Jade-1 stabilization is therefore the first VHL activity to show substantial correlation with renal cancer risk, suggesting it has a disease relationship. Moreover, stabilization of Jade-1 by VHL is highly specific, as it has not been observed with known or potential VHL partners. We have established convincing evidence of the VHL-Jade-1 relationship's authenticity as well as Jade-1's compelling biological significance. We propose the following Aims: 1. The VHL-Jade-1 protein-protein interaction, and Jade-1 expression in renal cancer tissue 2. VHL-dependent Jade-1 stabilization and modification 3. Examination of the role of Jade-1 in apoptosis and modulation by VHL

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA079830-07
Application #
7084646
Study Section
Pathology B Study Section (PTHB)
Program Officer
Yassin, Rihab R,
Project Start
1999-04-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
7
Fiscal Year
2006
Total Cost
$314,433
Indirect Cost

  Institution

Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118

  Publications

Zeng, Liling; Bai, Ming; Mittal, Amit K et al. (2013) Candidate tumor suppressor and pVHL partner Jade-1 binds and inhibits AKT in renal cell carcinoma. Cancer Res 73:5371-80
Foy, Rebecca L; Chitalia, Vipul C; Panchenko, Maria V et al. (2012) Polycystin-1 regulates the stability and ubiquitination of transcription factor Jade-1. Hum Mol Genet 21:5456-71
Chitalia, Vipul C; Foy, Rebecca L; Bachschmid, Markus M et al. (2008) Jade-1 inhibits Wnt signalling by ubiquitylating beta-catenin and mediates Wnt pathway inhibition by pVHL. Nat Cell Biol 10:1208-16
Foy, Rebecca L; Song, Ihn Young; Chitalia, Vipul C et al. (2008) Role of Jade-1 in the histone acetyltransferase (HAT) HBO1 complex. J Biol Chem 283:28817-26
Basu, Aninda; Contreras, Alan G; Datta, Dipak et al. (2008) Overexpression of vascular endothelial growth factor and the development of post-transplantation cancer. Cancer Res 68:5689-98
Zhou, Mina I; Foy, Rebecca L; Chitalia, Vipul C et al. (2005) Jade-1, a candidate renal tumor suppressor that promotes apoptosis. Proc Natl Acad Sci U S A 102:11035-40
Cohen, Herbert T; McGovern, Francis J (2005) Renal-cell carcinoma. N Engl J Med 353:2477-90
Zhou, Mina I; Wang, Hongmei; Foy, Rebecca L et al. (2004) Tumor suppressor von Hippel-Lindau (VHL) stabilization of Jade-1 protein occurs through plant homeodomains and is VHL mutation dependent. Cancer Res 64:1278-86
Panchenko, Maria V; Zhou, Mina I; Cohen, Herbert T (2004) von Hippel-Lindau partner Jade-1 is a transcriptional co-activator associated with histone acetyltransferase activity. J Biol Chem 279:56032-41
Zhou, Mina I; Wang, Hongmei; Ross, Jonathan J et al. (2002) The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1. J Biol Chem 277:39887-98

Showing the most recent 10 out of 11 publications