Alternative titles; symbols
HGNC Approved Gene Symbol: ST8SIA1
Cytogenetic location: 12p12.1 Genomic coordinates (GRCh38): 12:22,193,391-22,334,707 (from NCBI)
Gangliosides are membrane-bound glycosphingolipids containing sialic acids. The GD3 ganglioside is the first ganglioside in the b-series synthetic pathway and is highly expressed in the early stage of development in fetal rat brain and in human melanoma tissues and melanoma cell lines. Furthermore, the GD3 ganglioside has been shown to be important for cell adhesion and growth of cultured malignant cells. ST8SIA1, or GD3 synthase, catalyzes the formation of GD3 ganglioside by transfer of a sialic acid molecule from CMP-NeuAc to the terminal sialic acid of GM3 via an alpha 2-8 linkage (Sasaki et al., 1994).
Sasaki et al. (1994) used expression cloning to isolate a human cDNA for GD3 synthase. The cDNA encodes a 341-amino acid protein containing a single transmembrane domain in its N-terminal region. The amino acid sequence of GD3 synthase shows a high level of similarity with those of other sialyltransferases at 2 conserved regions, both of which are the so-called sialyl motif typical of the sialyltransferase family.
Ha et al. (2004) demonstrated that overexpression of GD3S in a human vascular endothelial cell line downregulated BCL2 (151430) and accelerated apoptosis. Western blot analysis detected reduced phosphorylation of AKT (see AKT1; 164730) and CREB (CREB1; 123810), and electrophoretic mobility shift assays indicated inhibited activation of CREB. Ha et al. (2004) concluded that GD3S has an apoptotic effect on human vascular endothelial cells by downregulating BCL2 expression via dephosphorylation of AKT and CREB.
Moon et al. (2004) found that overexpression of human GD3S in rodent vascular smooth muscle cells (VSMCs) in the presence of PDGF (see PDGFB; 190040) inhibited DNA synthesis and Erk (see MAPK3; 601795) phosphorylation. The inhibitory effects of GD3S overexpression correlated with downregulation of cyclin E (CCNE1; 123837), blockade of p27 (CDKN1B; 600778) inhibition, and upregulation of p21 (CDKN1A; 116899), a CDK inhibitor. Blocking GD3S function with anti-GD3 antibody rescued VSMC proliferation and expression of cell cycle proteins. Overexpression of GD3S in VSMCs also inhibited Tnfa (191160)-induced Mmp9 (120361) expression and decreased Mmp9 promoter activity in response to Tnfa. Overexpression of Mmp9 in GD3S-transfected cells rescued the proliferation defect caused by GD3S. Moon et al. (2004) concluded that GD3S is a modulator of VSMC proliferation.
Sasaki et al. (1994) assigned the ST8SIA1 gene to chromosome 12 by PCR analysis of somatic cell hybrids. Matsuda et al. (1996) localized the ST8SIA1 gene by fluorescence in situ hybridization to chromosome 12p12.1-p11.2. The murine gene was located by interspecific backcross analysis to mouse chromosome 6 in a region syntenic to 12p.
By successive rounds of gene targeting, Kawai et al. (1998) disrupted the Gd3s gene in mouse embryonic stem cells. Gd3s -/- cells did not synthesize b-series gangliosides, but they retained the ability to undergo neuronal differentiation.
Kawai et al. (2001) found that Gd3s -/- mice were viable and fertile, had normal growth, and showed no gross behavioral abnormalities. Histologic examination of brains from Gd3s -/- mice showed no observable demyelination. Double knockout of Gd3s and beta-1,4-N acetylgalactosaminyltransferase (GALGT; 601873) resulted in mice that expressed GM3 as their major ganglioside. These mice displayed sudden death and were extremely susceptible to induction of lethal seizures by sound stimuli.
Ha, K.-T., Lee, Y.-C., Kim, C.-H. Overexpression of GD3 synthase induces apoptosis of vascular endothelial ECV304 cells through downregulation of Bcl-2. FEBS Lett. 568: 183-187, 2004. [PubMed: 15196944] [Full Text: https://doi.org/10.1016/j.febslet.2004.05.020]
Kawai, H., Allende, M. L., Wada, R., Kono, M., Sango, K., Deng, C., Miyakawa, T., Crawley, J. N., Werth, N., Bierfreund, U., Sandhoff, K., Proia, R. L. Mice expressing only monosialoganglioside GM3 exhibit lethal audiogenic seizures. J. Biol. Chem. 276: 6885-6888, 2001. [PubMed: 11133999] [Full Text: https://doi.org/10.1074/jbc.C000847200]
Kawai, H., Sango, K., Mullin, K. A., Proia, R. L. Embryonic stem cells with a disrupted GD3 synthase gene undergo neuronal differentiation in the absence of b-series gangliosides. J. Biol. Chem. 273: 19634-19638, 1998. [PubMed: 9677390] [Full Text: https://doi.org/10.1074/jbc.273.31.19634]
Matsuda, Y., Nara, K., Watanabe, Y., Saito, T., Sanai, Y. Chromosome mapping of the GD3 synthase gene (SIAT8) in human and mouse. Genomics 32: 137-139, 1996. [PubMed: 8786103] [Full Text: https://doi.org/10.1006/geno.1996.0090]
Moon, S.-K., Kim, H.-M., Lee, Y.-C., Kim, C.-H. Disialoganglioside (GD3) synthase gene expression suppresses vascular smooth muscle cell responses via the inhibition of ERK1/2 phosphorylation, cell cycle progression, and matrix metalloproteinase-9 expression. J. Biol. Chem. 279: 33063-33070, 2004. [PubMed: 15175338] [Full Text: https://doi.org/10.1074/jbc.M313462200]
Sasaki, K., Kurata, K., Kojima, N., Kurosawa, N., Ohta, S., Hanai, N., Tsuji, S., Nishi, T. Expression cloning of a G(M3)-specific alpha-2,8-sialyltransferase (G(D3) synthase). J. Biol. Chem. 269: 15950-15956, 1994. [PubMed: 8195250]