DF/HCC Program Affiliation

Kidney Cancer

Research Abstract

One 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.

Publications

• Duffield JS, Park KM, Hsiao LL, Kelley VR, Scadden DT, Ichimura T, Bonventre JV.Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells.J Clin Invest 2005 Jul 1;115(7):1743-17
  16007251
• Ilsley JN, Nakanishi M, Flynn C, Belinsky GS, De Guise S, Adib JN, Dobrowsky RT, Bonventre JV, Rosenberg DW.Cytoplasmic phospholipase A2 deletion enhances colon tumorigenesis.Cancer Res 2005 Apr 1;65(7):2636-43.
  15805260
• Han WK, Alinani A, Wu CL, Michaelson D, Loda M, McGovern FJ, Thadhani R, Bonventre JV.Human kidney injury molecule-1 is a tissue and urinary tumor marker of renal cell carcinoma.J Am Soc Nephrol 2005 Apr;16(4):1126-34.
  15744000
• Park KM, Cho HJ, Bonventre JV.Orchiectomy reduces susceptibility to renal ischemic injury: a role for heat shock proteins.Biochem Biophys Res Commun 2005 Mar 4;328(1):312-7.
  15670785
• Hentschel DM, Park KM, Cilenti L, Zervos AS, Drummond I, Bonventre JV.Acute renal failure in zebrafish: a novel system to study a complex disease.Am J Physiol Renal Physiol 2005 May;288(5):F923-9.
  15625083
• Han WK, Bonventre JV.Biologic markers for the early detection of acute kidney injury.Curr Opin Crit Care 2004 Dec;10(6):476-82.
  15616389
• Sim KG, Zang Z, Yang CM, Bonventre JV, Hsu SI.TRIP-Br links E2F to novel functions in the regulation of cyclin e expression during cell cycle progression and in the maintenance of genomic stability.Cell Cycle 2004 Oct;3(10):1296-304.
  15467469
• Cilenti L, Kyriazis GA, Soundarapandian MM, Stratico V, Yerkes A, Park KM, Sheridan AM, Alnemri ES, Bonventre JV, Zervos AS.Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells.Am J Physiol Renal Physiol 2005 Feb;288(2):F371-9.
  15454391
• Park KM, Kim JI, Ahn Y, Bonventre AJ, Bonventre JV.Testosterone is responsible for enhanced susceptibility of males to ischemic renal injury.J Biol Chem 2004 Dec 10;279(50):52282-92.
  15358759
• Meyer AM, Dwyer-Nield LD, Hurteau GJ, Keith RL, O'Leary E, You M, Bonventre JV, Nemenoff RA, Malkinson AM.Decreased lung tumorigenesis in mice genetically deficient in cytosolic phospholipase A2.Carcinogenesis 2004 Aug;25(8):1517-24.
  15033900