SMG-1 as a Promising Tumor Suppressor in the Management of Cancers

Abstract

SMG-1 (Suppressor of Morphogenesis in Genitalia-1) is an evolutionally conserved serine/threonine-protein kinase and belongs Phosphatidylinositol-3-Kinase (PI3K) related kinases (PIKKs) that include Ataxia Telangiectasia Mutated (ATM), ATM and Rad3 Related (ATR), Mammalian Target of Rapamycin (mTOR), DNADependent Protein Kinase Catalytic Subunit (DNA-PKcs) and Transformation/Transcription Domain-Associated Protein (TRRAP) [1]. The deduced 3,521-amino acid protein has a calculated molecular mass of 410kD [2]. PIKKs have diverse functions. For example, ATM, ATR and DNA-PKcs are involved in the response to DNA damage. ATM and DNA-PKcs respond to DNA Double Strand Breaks (DSBs) and ATR to DNA replication blockers or formation of long stretches of single strand DNA [3]. mTOR is a nutrient-regulated kinase that controls a wide variety of pathways involved in metabolism and cell growth [4]. TRRAP functions as part of a multiprotein co-activator complex which is involved with the transcriptional activity of c-Myc and other transcriptional factors [5]. SMG-1 is a part of the mRNA surveillance complex that regulates Nonsense-Mediated mRNA Decay (NMD) [6]. SMG-1 was firstly reported as a member of the informational suppression in Caenorhabditis elegans (C. elegans) which affected several mRNA processes in 1989 [7]. Pulak et al. reported that loss of function mutations affecting seven C. elegans smg genes eliminates NMD [8] and later demonstrated that smg- 1 kinase activity was essential for NMD [9]. In 2001, Deming et al. reported a partial sequence of human SMG-1 as C. elegans SMG-1 related protein [10]. Yamashita et al. also reported the full-length sequence for human smg-1 which encoded a 3657 aa protein that was a novel PIKK and showed the involvement of SMG1 in mammalian NMD [11]. In 2004, Brumbaugh et al. reported the activation of SMG-1 by DNA damage and involvement of SMG-1 in genotoxic stress-induced phosphorylation of P53 [2]. Besides NMD, SMG- 1 roles as a protective agency in genotoxic stress such as radiation, tumor proliferation, and apoptosis. I will briefly summarize the roles of SMG-1 related with NMD and others in this paper.