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

Oliveira, Vasco; Romanow, William J.; Geisen, Christoph; Otterness, Diane M.; Mercurio, Frank; Wang, Hong Gang; Dalton, William S.; Abraham, Robert T.

doi:10.1074/jbc.m708008200

Cited by 39 publications

(58 citation statements)

References 29 publications

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“…Here, we examined four assays measuring NMD in a range of tissues or isolated cells; surprisingly, none of these assays showed evidence of any defect in NMD in Smg1 +/gt mice. Similarly, we found no defect in DNA damage responses in Smg1 +/gt mice despite SMG1 having a characterized role in these pathways (1,4,5,(7)(8)(9)(10). These data suggest that expression of Smg1 from a single allele is sufficient for full functionality of these pathways in the situations studied.…”

Section: Smg1supporting

confidence: 48%

“…Smg-1 in planarian worms can also act to regulate response to injury and growth via cross-talk with the PIKK family member mammalian target of rapamycin (6). Depletion of Smg1 in tumor cells markedly increased the extent of cell death induced by TNF-α or granzyme B (7,8). SMG1 kinase activity was also induced in response to hypoxia, where it negatively regulated hypoxia-inducible factor 1α (HIF-1α), in part, by blocking MAPK activation (9).…”

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confidence: 98%

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Smg1 haploinsufficiency predisposes to tumor formation and inflammation

Roberts

Luff

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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SMG1 is a member of the phosphoinositide kinase-like kinase family of proteins that includes ATM, ATR, and DNA-PK, proteins with known roles in DNA damage and cellular stress responses. SMG1 has a well-characterized role in nonsense-mediated decay as well as suggested roles in the DNA damage response, resistance to oxidative stress, regulation of hypoxic responses, and apoptosis. To understand the roles of SMG1 further, we generated a Genetrap Smg1 mouse model. Smg1 homozygous KO mice were early embryonic lethal, but Smg1 heterozygous mice showed a predisposition to a range of cancers, particularly lung and hematopoietic malignancies, as well as development of chronic inflammation. These mice did not display deficiencies in known roles of SMG1, including nonsensemediated decay. However, they showed elevated basal tissue and serum cytokine levels, indicating low-level inflammation before the development of tumors. Smg1 heterozygous mice also showed evidence of oxidative damage in tissues. These data suggest that the inflammation observed in Smg1 haploinsufficiency contributes to susceptibility to cancer and that Smg1-deficient animals represent a model of inflammation-enhanced cancer development.MG1 is an ∼400-kDa member of the phosphoinositide kinaselike kinase (PIKK) family of proteins (1). Other family members include ATM, ATR, and DNA-PK, which are known regulators of DNA damage and cellular stress responses. SMG1 has a well-characterized role in nonsense-mediated decay (NMD), a process that ensures the rapid degradation of mRNA containing premature termination codons (PTCs). It is important to eliminate these mRNAs to prevent production of truncated proteins that might interfere with the function of normal proteins in the cell. The importance of SMG1 activity for efficient NMD function is evident from markedly increased levels of PTC containing transcripts in the presence of kinase-dead SMG1 (1). Brumbaugh et al.(2) demonstrated that SMG1 is also functional in the genotoxic stress pathway. SMG1 was activated by UV and ionizing radiation (IR) to phosphorylate a p53 substrate as well as Upf1 in vitro. In cells treated with siRNA to Smg1, Chk2 and p53 were constitutively phosphorylated. Overall, the data suggested that SMG1 deficiency caused DNA damage and constitutive activation of ATM/ATR. SMG1 also plays a role in telomere stability by negatively regulating noncoding RNAs, known as telomeric repeat-containing RNA (TERRA), which associate with telomeres. Smg1 depletion increased the number of TERRA-positive chromosomes and resulted in telomere destabilization (3, 4). Additional less wellcharacterized roles for Smg1 have also been described. In Caenorhabditis elegans, using a candidate RNAi feeding screen for clones that lengthen lifespan, Masse et al. (5) reported that smg-1 inactivation increased lifespan. The effect of smg-1 inactivation on lifespan appeared to be unrelated to its NMD function but required the p53 tumor suppressor ortholog cep-1. Inactivation of smg-1 conferred resistance to oxidative stres...

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Section: Smg1supporting

confidence: 48%

mentioning

confidence: 98%

Smg1 haploinsufficiency predisposes to tumor formation and inflammation

Roberts

Luff

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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.…”

Section: Smg-8 and Smg-9 Are Involved In Nmdmentioning

confidence: 99%

“…In addition to NMD, SMG-1 has been shown to be involved in genotoxic and oxidative stress response pathways (Brumbaugh et al 2004;Gehen et al 2008) and TNFa-induced apoptosis (Oliveira et al 2008) as other members of the PIKK family, ATM (ataxia telangiectagia mutated) and ATR (ATM-and Rad3-related) (Shiloh 2003). Although these observations raise the question as to the similarity and difference between SMG-1 and other PIKKs, the nature and the regulatory mechanism of SMG-1 kinase remains poorly understood.…”

mentioning

confidence: 99%

SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay

Yamashita

Izumi²,

Kashima³

et al. 2009

Genes Dev.

222

317

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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.[Keywords: NMD; mRNA surveillance; UPF1; SMG-1; PIKK; translation termination; mRNP remodeling] Supplemental material is available at http://www.genesdev.org.

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“…Like ATM, ATR, and the DNA-dependent protein kinase catalytic subunit, Smg1 is linked to DNA damage responses (3,4). Smg1 may also function in telomere maintenance, responses to hypoxia, and TNF-α-induced apoptosis (5)(6)(7). In vitro, Smg1 has a critical role in the degradation of premature termination codon (PTC)-containing transcripts mediated by the nonsense-mediated mRNA decay (NMD) pathway (2,3,8).…”

mentioning

confidence: 99%

Smg1 is required for embryogenesis and regulates diverse genes via alternative splicing coupled to nonsense-mediated mRNA decay

McIlwain

Pan

Reilly

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

158

166

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Smg1 is a PI3K-related kinase (PIKK) associated with multiple cellular functions, including DNA damage responses, telomere maintenance, and nonsense-mediated mRNA decay (NMD). NMD degrades transcripts that harbor premature termination codons (PTCs) as a result of events such as mutation or alternative splicing (AS). Recognition of PTCs during NMD requires the action of the Upstream frameshift protein Upf1, which must first be phosphorylated by Smg1. However, the physiological function of mammalian Smg1 is not known. By using a gene-trap model of Smg1 deficiency, we show that this kinase is essential for mouse embryogenesis such that Smg1 loss is lethal at embryonic day 8.5. High-throughput RNA sequencing (RNA-Seq) of RNA from cells of Smg1-deficient embryos revealed that Smg1 depletion led to pronounced accumulation of PTC-containing splice variant transcripts from approximately 9% of genes predicted to contain AS events capable of eliciting NMD. Among these genes are those involved in splicing itself, as well as genes not previously known to be subject to AS-coupled NMD, including several involved in transcription, intracellular signaling, membrane dynamics, cell death, and metabolism. Our results demonstrate a critical role for Smg1 in early mouse development and link the loss of this NMD factor to major and widespread changes in the mammalian transcriptome.gene trap | Smg-1

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

Cited by 39 publications

References 29 publications

Smg1 haploinsufficiency predisposes to tumor formation and inflammation

Smg1 haploinsufficiency predisposes to tumor formation and inflammation

SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay

Smg1 is required for embryogenesis and regulates diverse genes via alternative splicing coupled to nonsense-mediated mRNA decay

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