1. ¹Proteologics Limited, Weizmann Science Park, Rehovot, Israel
2. ²Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
3. ³Department of Pathophysiology, Jilin University School of Basic Medicine, Changchun, P.R. China
4. ⁴Department of Urology, Carmel Medical Center, Haifa, Israel
5. ⁵Department of Pathology, Rhode Island Hospital and Brown University Medical School, Providence, RI, USA
6. ⁶Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA

Correspondence: Professor DV Kalvakolanu, Greenebaum Cancer Center, University of Maryland School of Medicine, 660 W. Redwood Street, Howard Hall Room 324, Baltimore, MD 21201, USA. E-mail: dkalvako@umaryland.edu

Received 9 February 2006; Revised 11 April 2006; Accepted 11 April 2006; Published online 29 May 2006.

Abstract

Gene associated with retinoid interferon-induced mortality (GRIM)-19, an inhibitor of transcription factor STAT3, was originally identified as a critical regulatory protein in a genetic screen that was designed to identify the gene products necessary for Interferon (IFN)-- and retinoic acid-induced cell death. Over expression of GRIM-19 activates cell death. Conversely, inactivation of its expression promotes cell growth. STAT3 is a transcription factor that regulates gene expression in response to multiple extra cellular growth factors. In contrast to its normal feedback inhibition, a constitutive activation of STAT3 has been documented in several tumors. Although many STAT3-inhibitors are described, their relevance to human cancer is unclear. In an attempt to define the molecular alterations associated with human renal cell carcinoma (RCC) using mass spectrometry, we have discovered that expression of GRIM-19 is lost or severely depressed in a number of primary RCC and in some urinogenital tumors. Using an RCC cell line, we show that down regulation of GRIM-19 promotes tumor growth via an augmentation of STAT3-dependent gene expression. These studies for the first time show a tumor-suppressor like activity of GRIM-19.