Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of end-stage renal disease. Loss of the polycystin-1 - polycystin-2 interaction is central to disease pathogenesis, but the precise mechanism of cyst formation remains unclear. Intriguingly, disordered renal tubule cell proliferation and apoptosis are consistent features of all the cystic renal diseases. Our laboratory has been closely studying the molecular basis of von HippeI-Lindau (VHL) renal disease, which includes a polycystic kidney phenotype. The similarities between the cystogenic pathways in VHL disease and ADPKD are striking. Jade-1 (gene for Apoptosis and Differentiation in Epithelia) encodes a short-lived, highly-regulated pro-apoptotic transcription factor that is stabilized by the VHL tumor suppressor. Jade-1 resides in prominent nuclear speckles and is most highly expressed in renal tubular epithelial cells. Intriguingly, the pattern of naturally occurring VHL mutations that stabilize Jade-1 suggest a correlation with VHL renal disease risk, which has not been previously described. Jade-1 protein alters the monolayer morphology of renal cells and promotes apoptosis that is blocked by VHL. Jade-1 may help propel a pre-apoptotic epithelial cell off a monolayer, promoting anoikis. Remarkably, wild-type polycystin-1 strongly regulates Jade-1 much like VHL, and this effect is blocked by a disease-causing polycystin-1 mutation in the coiled-coil domain that prevents interaction with polycystin-2. Moreover, Jade-1 is the target of a novel polycystin-1 dominant-negative mechanism. Thus, pro-apoptotic Jade-1 is downstream of both VHL and a common polycystin-1 / polycystin-2 regulatory pathway. Jade-1 may therefore be a central regulator of renal cyst formation in VHL disease and ADPKD, and perhaps in other cystic renal diseases. The Jade-1 - polycystin relationship in cystic disease will be explored through the following Aims:
AIM 1 : The mechanism of Jade-1 regulation by polycystin-1 AIM 2:Jade-1 effects on the cell cycle and modulation by polycystin-1 AIM 3: Direct role of Jade-1 in renal cyst formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067569-03
Application #
7049325
Study Section
Pathology A Study Section (PTHA)
Program Officer
Rasooly, Rebekah S
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2006
Total Cost
$311,289
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
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
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
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