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A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas

Oncogene volume 25, pages 7138–7147 (2006)Cite this article

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)-β- 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.

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Abbreviations

GRIM:

Gene associated with Retinoid Interferon induced Mortality

IFN:

Interferon

IP:

Immunoprecipitation

MALDI-TOF:

Matrix-Assisted Laser Desorption Ionization-Time of Flight

RA:

all-trans Retinoic acid

RCC:

Renal Cell Carcinoma

RLU:

Relative Light Units

WB:

Western blot

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Acknowledgements

DVK thanks the National cancer Institute for Grant support CA105005 and CA78286. SPR is supported by NIH grants ES11863 and HL66109.

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Authors and Affiliations

  1. Proteologics Limited, Weizmann Science Park, Rehovot, Israel

    I Alchanati, D Konforty, I Alroy & M B Resnick

  2. Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

    S C Nallar, P Sun, J Hu & D V Kalvakolanu

  3. Department of Pathophysiology, Jilin University School of Basic Medicine, Changchun, P.R. China

    L Gao & X Zhao

  4. Department of Urology, Carmel Medical Center, Haifa, Israel

    A Stein, E Yakirevich & M B Resnick

  5. Department of Pathology, Rhode Island Hospital and Brown University Medical School, Providence, RI, USA

    E Yakirevich & M B Resnick

  6. Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA

    S P Reddy

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  1. I Alchanati
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  2. S C Nallar
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  10. X Zhao
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Correspondence to D V Kalvakolanu.

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Alchanati, I., Nallar, S., Sun, P. et al. A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas. Oncogene 25, 7138–7147 (2006). https://doi.org/10.1038/sj.onc.1209708

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