Disease relevance of SMG1

• In this study, we evaluated the effects of NMD inhibition by siRNA-mediated knockdown of SMG-1 or Upf1 on the phenotype of Ullrich disease, an autosomal recessive congenital muscular dystrophy [1].

High impact information on SMG1

• Importantly, an association between SURF and the EJC is required for SMG-1-mediated Upf1 phosphorylation and NMD [2].
• Thus, the SMG-1-mediated phosphorylation of Upf1 occurs on the association of SURF with EJC, which provides the link between the EJC and recognition of PTCs and triggers NMD [2].
• We also show that inhibitors of hSMG-1 induce the accumulation of truncated p53 proteins in human cancer cell lines with p53 PTC mutation [3].
• In particular, overexpression of a kinase-deficient point mutant of hSMG-1, hSMG-1-DA, results in a marked suppression of the PTC-dependent beta-globin mRNA degradation; whereas that of wild-type hSMG-1 enhances it [3].
• Here, we characterize the newest PIKK family member, hSMG-1, as a genotoxic stress-activated protein kinase that displays some functional overlap with the related kinase, ATM, in human cells [4].

Biological context of SMG1

• Intriguingly, SMG1 and EST1A/SMG6 function also in DNA repair and telomere maintenance, respectively [5].
• The duplication contains a second putative gene family (KIAA0220/SMG1) that is represented approximately eight times within the human genome [6].
• We propose that sequential phosphorylation and dephosphorylation of hUPF1 by hSMG-1 and PP2A, respectively, contribute to the remodeling of the mRNA surveillance complex [7].
• Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay [3].
• Gene disruption studies of one embedded gene (SMG1) corroborate that this region is duplicated in an otherwise haploid genome [8].

Anatomical context of SMG1

• Specific inhibition of nonsense-mediated mRNA decay components, SMG-1 or Upf1, rescues the phenotype of ullrich disease fibroblasts [1].
• In the present study, primary hepatocytes isolated from transgenic mice that possess the HBV X gene under the control of the human alpha-1-antitrypsin regulatory region (ATX mice) were found to be deficient in their ability to conduct unscheduled DNA synthesis in response to UV-induced DNA damage [9].
• We also used alpha-toxin (ATX), which makes smaller pores in the plasma membrane than SLO and depletes cytosolic ATP without BSA-dependent S1P leakage [10].
• In the present study, the focal application of anemone toxin II (ATX, 300 nM), which slows Na-channel inactivation, produced prolonged depolarizing after-potentials and, coincidentally, induced spontaneous bursting impulse activity that propagated away from the site of ATX application in the frog sciatic nerve in vitro [11].
• Phosphodiesterase-Ialpha/autotaxin (PD-Ialpha/ATX): a multifunctional protein involved in central nervous system development and disease [12].

Associations of SMG1 with chemical compounds

• SMG-1, a member of the PIKK (phosphoinositide 3-kinase related kinases) family, plays a critical role in the mRNA quality control system termed nonsense-mediated mRNA decay (NMD) [13].
• The application of low concentrations of lidocaine (1-10 microM), both at the site of ATX exposure and at a distant site, selectively and reversibly inhibited the spontaneous bursting, while having no effect on the electrically stimulated initial spike of the compound action potential [11].
• Ca(2+) also stimulated S1P release from ATX platelets without ATP, whereas the Ca(2+)-induced release was not inhibited by glyburide [10].
• Resveratrol and quercetin also blocked late I(Na) induced by the toxin, ATX II, with IC(50)s of 26.1 muM and 24.9 muM, respectively [14].
• Combined action of intraaxonal iodate and external sea anemone toxin ATX II on sodium channel inactivation of frog nerve fibres [15].

Enzymatic interactions of SMG1

• Our data indicate that hSMG-1 may function in NMD by directly phosphorylating hUpf1 protein at physiologically relevant sites [16].

Other interactions of SMG1

• Finally, NMD is suppressed in hSMG-1- but not ATM-deficient cells [4].
• Expression of hSMG-1 is required for optimal p53 activation after cellular exposure to genotoxic stress, and depletion of hSMG-1 leads to spontaneous DNA damage and increased sensitivity to ionizing radiation (IR) [4].
• Mammalian cells express six PIKK family members, five of which-ATM, ATR, mTOR, DNA-PK, and hSMG-1-function as protein serine-threosine kinases [17].
• Among those were genes both with known (set, ND4, SMG-1) and unknown functions [18].

Analytical, diagnostic and therapeutic context of SMG1

References