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Tumor-Suppressive Activity of the Cell Death Activator GRIM-19 on a Constitutively Active Signal Transducer and Activator of Transcription 3

¹ Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine; ² Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland; and ³ Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, Ohio

Requests for reprints: Dhananjaya V. Kalvakolanu, University of Maryland Cancer Center, Howard Hall, Room 324, 660 W. Redwood Street, Baltimore, MD 21201. Phone: 410-328-1396; Fax: 410-328-6559; E-mail: dkalvako{at}umaryland.edu.

Signal transducers and activators of transcription 3 (STAT3) was originally identified as a transcription factor that mediates cytokine-induced responses. In these pathways, Janus-activated kinase (JAK)–induced transient tyrosine phosphorylation of STAT3 promotes gene expression in response to a number of cytokines, which is inhibited by feedback mechanisms. A number of studies have shown that STAT3 is constitutively activated in human cancer cells, leading to cell proliferation. It is unclear, apart from a chronic tyrosyl phosphorylation of STAT3, what mechanisms contribute to the STAT3 deregulation in tumors. Earlier, we have isolated a novel growth inhibitory gene product, gene associated with retinoid-IFN–induced mortality 19 (GRIM-19), using a genetic approach. GRIM-19 is an IFN/retinoic acid–regulated growth suppressor. Subsequent analyses have shown that GRIM-19 binds to STAT3 and prevents interleukin-6–induced transcription of cellular genes. However, its effects on a constitutively active STAT3 and cellular transformation are unknown. In this study, we show that GRIM-19 suppresses constitutive STAT3-induced cellular transformation in vitro and in vivo by down-regulating the expression of a number of cellular genes involved in cell proliferation and apoptosis. [Cancer Res 2007;67(13):6212–20]

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