Joseph V. Bonventre, MD, PhD
Samuel A. Levine Professor of Medicine, Department of Medicine, Harvard Medical School
Professor, Harvard-MIT Health Sciences and Technology, Brigham And Women's Hospital
Director, Health Sciences and Technology, Massachusetts General Hospital
Chief, Renal Division, Medicine, Brigham And Women's Hospital
DF/HCC Program AffiliationKidney Cancer
Research AbstractOne focus of the lab is on Kidney injury molecule-1 which is markedly upregulated in renal cell carcinoma and other conditions where the kidney proximal epithelial cell is dedifferentiated. We are studying the functional role of this protein and its role as a urinary biomarker for renal cell carcinoma and renal epithelial cell injury. Another focus is on phospholipase A2 (PLA2) and the role of this family of enzymes on carcinogenesis, acute tissue injury, apoptosis, signal transduction and transcriptional regulation. We have created a cPLA2 null mouse and are studying the effects of absence of this gene on bowel cancer development in mice carrying the Min mutation as well as angiogenesis and tumor growth in the cPLA2 -/- mouse . Studies are carried to understand how phospholipases A2 contribute to apoptosis, to evaluate the importance of kinases such as the stress-activated MAP protein kinases, and the proteins interacting with cPLA2 to potentiate cell death, and to identify and characterize transcription factors that play important roles in the cell cycle. We have isolated a nuclear protein that interacts with the cytosolic 85 kDa cPLA2 and potentiates apoptosis. Gene therapy approaches with adenovirus are being used.
We have isolated a cDNA encoding TRIP-Br1, a novel transcriptional regulator which interacts with the PHD-bromodomain of the co-repressors of KRAB-mediated repression, KRIP-1(TIF1?) and TIF1?, as well as the co-activator/adaptor p300/CBP. TRIP-Br proteins make a direct functional contact with DP-1, resulting in the stimulation of E2F-1/DP-1 transcriptional activity. In this novel context, KRIP-1 cooperates with TRIP-Br proteins to co-activate E2F-1/DP-1. Co-expression of the retinoblastoma gene product (RB) abolishes baseline E2F-1/DP-1 transcriptional activity as well as TRIP-Br/KRIP-1 co-activation, both of which are restored in the presence of the E1A oncoprotein. These features suggest that TRIP-Br proteins function at E2F-responsive promoters to integrate regulatory signals provided by PHD zinc finger- and/or bromodomain-containing transcription factors such as KRIP-1 and p300/CBP.