Gene interactions and pathways from curated databases and text-mining
J Pharmacol Exp Ther 2004, PMID: 15169830

Insulin signaling regulates gamma-glutamylcysteine ligase catalytic subunit expression in primary cultured rat hepatocytes.

Kim, Sang K; Woodcroft, Kimberley J; Khodadadeh, Sarah S; Novak, Raymond F

Decreased glutathione (GSH) levels and gamma-glutamylcysteine ligase (GCL) activity have been observed in diabetic patients, and insulin reportedly increases GSH synthesis via increased GCL catalytic subunit (GCLC) gene expression. The signaling pathways responsible for mediating insulin effects on GCLC expression and GSH levels, however, are unknown. The signaling pathways involved in the regulation of GSH synthesis in response to insulin were examined in primary cultured rat hepatocytes. GSH levels, GCL activity, GCLC protein, and mRNA levels were increased to 140, 160, 600, and 340% of that monitored in untreated cells, respectively, in hepatocytes cultured with 100 nM insulin. The phosphatidylinositol 3-kinase (PI3K) inhibitors, wortmannin and LY294002 [2-(4-morpholinyl)-9-phenyl-4H-1-benzopyran-4-one], dominant-negative Akt, or rapamycin, an inhibitor of mTOR (mammalian target of rapamycin) and ribosomal p70 S6 kinase (p70S6K) phosphorylation, inhibited the insulin-mediated increase in GCLC protein and GSH levels. Although the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase, p38 MAPK, and JNK (c-Jun N-terminal kinase) were activated in response to insulin, PD98059 (2'-amino-3'-methoxyflavone), an inhibitor of mitogen-activated protein kinase kinase, SP600125 (1,9-pyrazoloanthrone), an inhibitor of JNK, and SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole], an inhibitor of p38 MAPK, failed to inhibit the insulin-mediated increase in GCLC protein levels. In conclusion, these data show that insulin signaling pathways involving PI3K/Akt/p70S6K, but not MAPKs, are active in the insulin-mediated regulation of GSH synthesis via increased GCLC expression.

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Text Mining Data

GCLC — insulin: " The signaling pathways responsible for mediating insulin effects on GCLC expression and GSH levels, however, are unknown "

mTOR ⊣ Akt: " The phosphatidylinositol 3-kinase (PI3K) inhibitors, wortmannin and LY294002 [ 2- ( 4-morpholinyl ) -9-phenyl-4H-1-benzopyran-4-one ], dominant negative Akt , or rapamycin, an inhibitor of mTOR ( mammalian target of rapamycin ) and ribosomal p70 S6 kinase (p70S6K) phosphorylation, inhibited the insulin mediated increase in GCLC protein and GSH levels "

GCLC ⊣ Akt: " The phosphatidylinositol 3-kinase (PI3K) inhibitors, wortmannin and LY294002 [ 2- ( 4-morpholinyl ) -9-phenyl-4H-1-benzopyran-4-one ], dominant negative Akt , or rapamycin, an inhibitor of mTOR ( mammalian target of rapamycin ) and ribosomal p70 S6 kinase (p70S6K) phosphorylation, inhibited the insulin mediated increase in GCLC protein and GSH levels "

p70 S6 kinase (p70S6K) ⊣ Akt: " The phosphatidylinositol 3-kinase (PI3K) inhibitors, wortmannin and LY294002 [ 2- ( 4-morpholinyl ) -9-phenyl-4H-1-benzopyran-4-one ], dominant negative Akt , or rapamycin, an inhibitor of mTOR ( mammalian target of rapamycin ) and ribosomal p70 S6 kinase (p70S6K) phosphorylation, inhibited the insulin mediated increase in GCLC protein and GSH levels "

mTOR → phosphatidylinositol 3-kinase (PI3K): " The phosphatidylinositol 3-kinase (PI3K) inhibitors, wortmannin and LY294002 [ 2- ( 4-morpholinyl ) -9-phenyl-4H-1-benzopyran-4-one ], dominant negative Akt, or rapamycin, an inhibitor of mTOR ( mammalian target of rapamycin ) and ribosomal p70 S6 kinase (p70S6K) phosphorylation, inhibited the insulin mediated increase in GCLC protein and GSH levels "

GCLC → insulin: " The phosphatidylinositol 3-kinase (PI3K) inhibitors, wortmannin and LY294002 [ 2- ( 4-morpholinyl ) -9-phenyl-4H-1-benzopyran-4-one ], dominant negative Akt, or rapamycin, an inhibitor of mTOR ( mammalian target of rapamycin ) and ribosomal p70 S6 kinase (p70S6K) phosphorylation, inhibited the insulin mediated increase in GCLC protein and GSH levels "

GCLC → phosphatidylinositol 3-kinase (PI3K): " The phosphatidylinositol 3-kinase (PI3K) inhibitors, wortmannin and LY294002 [ 2- ( 4-morpholinyl ) -9-phenyl-4H-1-benzopyran-4-one ], dominant negative Akt, or rapamycin, an inhibitor of mTOR ( mammalian target of rapamycin ) and ribosomal p70 S6 kinase (p70S6K) phosphorylation, inhibited the insulin mediated increase in GCLC protein and GSH levels "

p70 S6 kinase (p70S6K) → phosphatidylinositol 3-kinase (PI3K): " The phosphatidylinositol 3-kinase (PI3K) inhibitors, wortmannin and LY294002 [ 2- ( 4-morpholinyl ) -9-phenyl-4H-1-benzopyran-4-one ], dominant negative Akt, or rapamycin, an inhibitor of mTOR ( mammalian target of rapamycin ) and ribosomal p70 S6 kinase (p70S6K) phosphorylation, inhibited the insulin mediated increase in GCLC protein and GSH levels "

GCLC → insulin: " Although the mitogen activated protein kinases ( MAPKs ) extracellular signal regulated kinase, p38 MAPK, and JNK ( c-Jun N-terminal kinase ) were activated in response to insulin, PD98059 ( 2'-amino-3'-methoxyflavone ), an inhibitor of mitogen activated protein kinase kinase, SP600125 ( 1,9-pyrazoloanthrone ), an inhibitor of JNK, and SB203580 [ 4- ( 4-fluorophenyl ) -2- ( 4-methylsulfinylphenyl ) -5- ( 4-pyridyl ) 1H-imidazole ], an inhibitor of p38 MAPK, failed to inhibit the insulin mediated increase in GCLC protein levels "

Manually curated Databases

No curated data.