期刊
PROTEOMICS
卷 12, 期 12, 页码 2024-2035出版社
WILEY
DOI: 10.1002/pmic.201100666
关键词
Animal proteomics; Cancer; Endoplasmic reticulum; Liver proteins; Oxidative stress; Two-dimensional differential in-gel electrophoresis
资金
- Japan Society for the Promotion of Science (JSPS)
- Japan Ministry of Education, Culture, Sports and Technology (MEXT) [08107960, 09153695]
- National Institutes of Health of the United States [R01CA55578, R01CA122359, P01CA123328]
- Grants-in-Aid for Scientific Research [20117008] Funding Source: KAKEN
S-Nitrosoglutathione reductase (GSNOR) is a key regulator of protein S-nitrosylation, the covalent modification of cysteine residues by nitric oxide that can affect activities of many proteins. We recently discovered that excessive S-nitrosylation from GSNOR deficiency in mice under inflammation inactivates the key DNA repair protein O6-alkylguanine-DNA alkyltransferase and promotes both spontaneous and carcinogen-induced hepatocellular carcinoma. To explore further the mechanism of tumorigenesis due to GSNOR deficiency, we compared the protein expression profiles in the livers of wild-type and GSNOR-deficient (GSNOR-/-) mice that were challenged with lipopolysaccharide to induce inflammation and expression of inducible nitric oxide synthase (iNOS). Two-dimensional difference gel electrophoresis analysis identified 38 protein spots of significantly increased intensity and 31 protein spots of significantly decreased intensity in the GSNOR-/- mice compared to those in the wild-type mice. We subsequently identified 19 upregulated and 19 downregulated proteins in GSNOR-/- mice using mass spectrometry. Immunoblot analysis confirmed in GSNOR-/- mice a large increase in the expression of the pro-inflammatory mediator S100A9, a protein previously implicated in human liver carcinogenesis. We also found a decrease in the expression of multiple members of the protein disulfide-isomerase (PDI) family and an alteration in the expression pattern of the endoplasmic reticulum (ER) chaperones in GSNOR-/- mice. Furthermore, altered expression of these proteins from GSNOR deficiency was prevented in mice lacking both GSNOR and iNOS. In addition, we detected S-nitrosylation of two members of the PDI protein family. These results suggest that S-nitrosylation resulting from GSNOR deficiency may promote carcinogenesis under inflammatory conditions in part through the disruption of inflammatory and ER stress responses.
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