A protective role for the human SMG-1 kinase against tumor necrosis factor-alpha-induced apoptosis

Department of Experimental Therapeutics, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, Florida 33612, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2008; 283(19):13174-84. DOI: 10.1074/jbc.M708008200
Source: PubMed


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.

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    • "For example, UPF1 has been shown to directly participate in mRNA decay pathways besides NMD and also to help maintain genome stability (Kaygun and Marzluff, 2005; Azzalin and Lingner, 2006; Kim et al., 2007). SMG1 functions directly in DNA surveillance by participating in genotoxic stress response pathways (Brumbaugh et al., 2004; Oliveira et al., 2008). Both SMG1 and UPF1, along with SMG6, have roles in telomere maintenance (Reichenbach et al., 2003). "
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    ABSTRACT: Nonsense-mediated mRNA decay (NMD) is a conserved RNA decay pathway that degrades aberrant mRNAs and directly regulates many normal mRNAs. This dual role for NMD raises the possibility that its magnitude is buffered to prevent the potentially catastrophic alterations in gene expression that would otherwise occur if NMD were perturbed by environmental or genetic insults. In support of this, here we report the existence of a negative feedback regulatory network that directly acts on seven NMD factors. Feedback regulation is conferred by different branches of the NMD pathway in a cell type-specific and developmentally regulated manner. We identify feedback-regulated NMD factors that are rate limiting for NMD and demonstrate that reversal of feedback regulation in response to NMD perturbation is crucial for maintaining NMD. Together, our results suggest the existence of an intricate feedback network that maintains both RNA surveillance and the homeostasis of normal gene expression in mammalian cells.
    Full-text · Article · Sep 2011 · Molecular cell
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    • "We propose that several SMG-9 containing complexes that do not contain SMG-1 could potentially have biological functions apart from SMG1C. Thus, SMG-1 has been shown to participate in the cellular stress response (14,16–18), and we find that the expression of truncated versions of SMG-9 increased the susceptibility to apoptosis (Supplementary Figure S4). In addition, we speculate that SMG-9:SMG-9 and, probably, SMG-8:SMG-9 complexes could function as intermediaries mediating the assembly of SMG1C. "
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    ABSTRACT: SMG-9 is part of a protein kinase complex, SMG1C, which consists of the SMG-1 kinase, SMG-8 and SMG-9. SMG1C mediated phosphorylation of Upf1 triggers nonsense-mediated mRNA decay (NMD), a eukaryotic surveillance pathway that detects and targets for degradation mRNAs harboring premature translation termination codons. Here, we have characterized SMG-9, showing that it comprises an N-terminal 180 residue intrinsically disordered region (IDR) followed by a well-folded C-terminal domain. Both domains are required for SMG-1 binding and the integrity of the SMG1C complex, whereas the C-terminus is sufficient to interact with SMG-8. In addition, we have found that SMG-9 assembles in vivo into SMG-9:SMG-9 and, most likely, SMG-8:SMG-9 complexes that are not constituents of SMG1C. SMG-9 self-association is driven by interactions between the C-terminal domains and surprisingly, some SMG-9 oligomers are completely devoid of SMG-1 and SMG-8. We propose that SMG-9 has biological functions beyond SMG1C, as part of distinct SMG-9-containing complexes. Some of these complexes may function as intermediates potentially regulating SMG1C assembly, tuning the activity of SMG-1 with the NMD machinery. The structural malleability of IDRs could facilitate the transit of SMG-9 through several macromolecular complexes.
    Full-text · Article · Jan 2011 · Nucleic Acids Research
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    • "Finally, we revealed the biochemical nature of the SMG1C with two regulatory subunits, SMG-8 and SMG-9. In addition to NMD, SMG-1 is involved in genome surveillance, telomere maintenance, the suppression of TNFa-induced apoptosis and hyperoxia-induced p53 activation (Brumbaugh et al. 2004; Chen et al. 2006; Azzalin et al. 2007; Gehen et al. 2008; Oliveira et al. 2008). Further analysis of the roles of the SMG1C will accelerate the understanding of the mechanism underlying the responses of cells against various stresses. "
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    ABSTRACT: Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that detects and degrades mRNAs containing premature translation termination codons (PTCs). SMG-1 and Upf1 transiently form a surveillance complex termed "SURF" that includes eRF1 and eRF3 on post-spliced mRNAs during recognition of PTC. If an exon junction complex (EJC) exists downstream from the SURF complex, SMG-1 phosphorylates Upf1, the step that is a rate-limiting for NMD. We provide evidence of an association between the SURF complex and the ribosome in association with mRNPs, and we suggest that the SURF complex functions as a translation termination complex during NMD. We identified SMG-8 and SMG-9 as novel subunits of the SMG-1 complex. SMG-8 and SMG-9 suppress SMG-1 kinase activity in the isolated SMG-1 complex and are involved in NMD in both mammals and nematodes. SMG-8 recruits SMG-1 to the mRNA surveillance complex, and inactivation of SMG-8 induces accumulation of a ribosome:Upf1:eRF1:eRF3:EJC complex on mRNP, which physically bridges the ribosome and EJC through eRF1, eRF3, and Upf1. These results not only reveal the regulatory mechanism of SMG-1 kinase but also reveal the sequential remodeling of the ribosome:SURF complex to the predicted DECID (DECay InDucing) complex, a ribosome:SURF:EJC complex, as a mechanism of in vivo PTC discrimination.
    Full-text · Article · Jun 2009 · Genes & development
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