Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cells subjected to glycated collagen I develop premature senescence within 3-5 days, as revealed by increased senescence-associated beta-galactosidase activity, decreased proliferation, and an increase in cell size. Here, we analyzed the time course and possible mechanisms of this process. Lysosomal integrity studies revealed a rapid collapse of pH gradient and lysosomal permeabilization, detectable after 30 min, and preceded by the increased production of reactive oxygen species. Measurement of mitochondrial membrane potential after application of glycated collagen demonstrated that depolarization was delayed by 4 h compared with changes in lysosomal pH and permeability. Based on the above findings of lysosomal permeabilization, we hypothesized that the reduced activity of senescence-associated beta-galactosidase could be responsible for the cellular accumulation of gangliosides, previously shown to induce cell senescence. After 5 days of exposure to glycated collagen, there was an increase in the levels of gangliosides GM3, GD1b, and GT1b, coincident with development of cell senescence. Treatment of endothelial cells with d-threo-EtDOP4, an inhibitor of glucosylceramide synthase, inhibited apoptosis, but not the development of senescence. In conclusion, collagen I modified by advanced glycation initially induces apoptosis of human umbilical vein endothelial cells. This process is initiated by the collapse of lysosomal pH and an increase in lysosomal permeability, with the subsequent mitochondrial depolarization and accumulation of gangliosides. Blockade of ganglioside synthesis suppresses apoptosis, but not senescence, which develops after 3 days of exposure to glycated collagen. These data imply a critical role for lysosomal permeabilization in triggering apoptosis of endothelial cells exposed to the diabetic milieu.
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PMID:Mapping mechanisms and charting the time course of premature cell senescence and apoptosis: lysosomal dysfunction and ganglioside accumulation in endothelial cells. 1792 15

Epidermal growth factor receptor (EGFR), an N-glycosylated transmembrane protein with an intracellular kinase domain, undergoes dimerization by ligand binding resulting in activation of the kinase domain and phosphorylation. Ganglioside GM3 containing sialyllactose inhibits the tyrosine kinase activity of EGFR through carbohydrate to carbohydrate interactions (CCI) between N-glycans with GlcNAc termini on EGFR and oligosaccharides on GM3. In this study, we provide further evidence for CCI between EGFR and GM3. (i) In vitro and in situ, the inhibitory effect of GM3 on EGFR tyrosine kinase was much higher in A431 cells upon exposure of the GlcNAc termini of the N-glycans to glycosidase treatment (neuraminidase and beta-galactosidase) than in untreated A431 cells. Furthermore, the GM3-mediated inhibition was abrogated by co-incubation with N-glycan containing terminal GlcNAc. (ii) In situ, inhibition of EGFR phosphorylation by GM3 was not observed in alpha-mannosidase IB (ManIB)-knocked down A431 cells that accumulate high mannose-type N-glycans. (iii) EGFR binding to GM3 was enhanced in glycosidase-treated cells that accumulated GlcNAc termini, whereas GM3 did not bind to EGFR from ManIB-knocked down cells that accumulated high mannose-type N-glycans. These results indicate that GM3-mediated inhibition of EGFR phosphorylation is caused by interaction of GM3 with GlcNAc-terminated N-glycan on EGFR.
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PMID:Tyrosine kinase activity of epidermal growth factor receptor is regulated by GM3 binding through carbohydrate to carbohydrate interactions. 1912 64

Small intestinal epithelial cells are rich in characteristic glycosphingolipids (GSLs) that are composed of phytosphingosine and alpha-hydroxy fatty acid, but the physiological roles of GSLs in the small intestine remain unclear. Here, we report the developmental changes in GSL composition in the mouse small intestine (duodenum through ileum) and their relationship with the temporal mRNA expression of nutrient transporters. Up to 2 weeks after birth, the major GSLs were hexosylceramide (HexCer), GM3, GM1 and GD1a. After 2 weeks of age, HexCer and asialo GM1 became the major GSLs. The ceramide moiety of both HexCer and asialo GM1 was composed mainly of phytosphingosine and alpha-hydroxy fatty acid, from birth through adulthood. Immunohistochemically, GM1 localized in the cytoplasm, and asialo GM1 localized exclusively in the apical microvillous membrane of small intestinal epithelial cells. The shift from sialylated GSLs to asialo GM1 was achieved by the combinational and tissue-specific transcriptional down-regulation of GM3 synthase and GM1-beta-galactosidase at around 2 weeks of age. The temporal mRNA expression of various nutrient transporters also showed significant changes at around 2 weeks of age, including the up-regulation of the sodium/glucose cotransporter and the oligopeptide transporter, as well as the down-regulation of amino acid transporters. These synchronized changes in the mRNA expression of nutrient transporters with GSL composition during suckling-to-weanling transition suggest the contributions of GSLs to morphologic and functional development in the membrane of mouse small intestinal epithelial cells.
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PMID:Developmental changes in glycolipids and synchronized expression of nutrient transporters in the mouse small intestine. 1926 55


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