title: Anti-diabetic and anti-obesity agent sodium tungstate enhances GCN pathway activation through Glc7p inhibition.
abstract: Tungstate counteracts diabetes and obesity in animal models, but its molecular mechanisms remain elusive. Our Saccharomyces cerevisiae-based approach has found that tungstate alleviated the growth defect induced by nutrient stress and enhanced the activation of the GCN pathway. Tungstate relieved the sensitivity to starvation of a gcn2-507 yeast hypomorphic mutant, indicating that tungstate modulated the GCN pathway downstream of Gcn2p. Interestingly, tungstate inhibited Glc7p and PP1 phosphatase activity, both negative regulators of the GCN pathway in yeast and humans, respectively. Accordingly, overexpression of a dominant-negative Glc7p mutant in yeast mimicked tungstate effects. Therefore tungstate alleviates nutrient stress in yeast by in vivo inhibition of Glc7p. These data uncover a potential role for tungstate in the treatment of PP1 and GCN related diseases.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain. carlospu77@gmail.com
authors.forename: C J
authors.initials: CJ
authors.lastname: Rodriguez-Hernandez
authors.forename: J J
authors.initials: JJ
authors.lastname: Guinovart
authors.forename: J R
authors.initials: JR
authors.lastname: Murguia
mesh_terms: D000596:Amino Acids / Q000172:deficiency; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004357:Drug Synergism; D005502:Food; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D009154:Mutation; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D016559:Tacrolimus / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology; D017973:Tungsten Compounds / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D019440:Anti-Obesity Agents; D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D029701:Saccharomyces cerevisiae Proteins; D014230:Triazoles; D017973:Tungsten Compounds; C025399:sodium tungstate(VI); C512912:GCN2 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C092048:GLC7 protein, S cerevisiae; D054645:Protein Phosphatase 1; D016559:Tacrolimus