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

• Published in: The Journal of biological chemistry 2008-05, Vol.283 (19), p.13174-13184
• Main Authors: Oliveira, Vasco, Romanow, William J., Geisen, Christoph, Otterness, Diane M., Mercurio, Frank, Wang, Hong Gang, Dalton, William S., Abraham, Robert T.
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism; Cell Line, Tumor; Cytoprotection - drug effects; Death Domain Receptor Signaling Adaptor Proteins - metabolism; Humans; NF-kappa B - metabolism; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Protein Biosynthesis - genetics; Protein Serine-Threonine Kinases; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M708008200

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-α (TNFα) stimulation. The increase in TNFα-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 TNFα-induced NF-κB activation. Rather, we observed that loss of hSMG-1 accelerates the degradation of the long form of the FLICE-inhibitory protein (FLIPL), an inhibitor of death-inducing signaling complex-mediated caspase-8 activation, in TNFα-treated cells. These results suggest that hSMG-1 plays an important role in cell survival during TNFα-induced stress.