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J. Biol. Chem., Vol. 283, Issue 19, 13174-13184, May 9, 2008

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A Protective Role for the Human SMG-1 Kinase against Tumor Necrosis Factor--induced Apoptosis^*

Vasco Oliveira¹, William J. Romanow, Christoph Geisen^¶, Diane M. Otterness^||, Frank Mercurio, Hong Gang Wang, William S. Dalton, and Robert T. Abraham^||2

From the Department of Experimental Therapeutics, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, Florida 33612, the Discovery Biology Group, Signal Pharmaceuticals, LLC, San Diego, California 92121, the ^¶Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, and ^||The Burnham Institute for Medical Research, La Jolla, California 92038

The human suppressor of morphogenesis in genitalia-1 (hSMG-1) protein kinase plays dual roles in mRNA surveillance and genotoxic stress response pathways in human cells. Here, we report that small interfering RNA-mediated depletion of hSMG-1, but not ATM, ATR, hUpf1, or hUpf2, in human U2OS osteosarcoma cells markedly increases the magnitude and accelerates the rate of apoptosis induced by tumor necrosis factor- (TNF) stimulation. The increase in TNF-mediated cell killing observed in hSMG-1-depleted cells is not related to the suppression of nonsense-mediated mRNA decay or to the inhibition of TNF-induced NF-B activation. Rather, we observed that loss of hSMG-1 accelerates the degradation of the long form of the FLICE-inhibitory protein (FLIP_L), an inhibitor of death-inducing signaling complex-mediated caspase-8 activation, in TNF-treated cells. These results suggest that hSMG-1 plays an important role in cell survival during TNF-induced stress.

Received for publication, September 25, 2007 , and in revised form, February 5, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants CA97950 and CA2 P30 CA076292-10. This work was also supported by the Ataxia-Telangiectasia Children's Project, Johnson & Johnson, Department of Defense Grant DAMD17-02-1-0730, and the Molecular Biology Core Facility at the H. Lee Moffitt Cancer Center & Research Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ Supported by a postdoctoral fellowship from the Portuguese Fundação para a Ciência e a Tecnologia (Grant SFRH/BPD/20773/2004).

² To whom correspondence should be addressed: Dept. of Experimental Therapeutics and Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Instit., University of South Florida, 12902 Magnolia Dr., Tampa, FL 33612. Tel.: 813-745-4361; Fax: 813-745-4258; E-mail: william.dalton{at}moffitt.org.

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