Dual specificity MAPK phosphatase 3 activates PEPCK gene transcription and increases gluconeogenesis in rat hepatoma cells.
Insulin is a key hormone that controls glucose homeostasis. In liver, insulin suppresses gluconeogenesis by inhibiting the transcriptions of phosphoenolpyruvate carboxylase (PEPCK) and glucose-6-phosphatase (G6Pase) genes. In insulin resistance and type II diabetes there is an elevation of hepatic gluconeogenesis, which contributes to hyperglycemia. To search for novel genes that negatively regulate insulin signaling in controlling metabolic pathways, we screened a cDNA library derived from the white adipose tissue of ob/ob mice using a reporter system comprised of the PEPCK promoter placed upstream of the alkaline phosphatase gene. The mitogen-activated dual specificity protein kinase phosphatase 3 (MKP-3) was identified as a candidate gene that antagonized insulin suppression on PEPCK gene transcription from this screen. In this study, we showed that MKP-3 was expressed in insulin-responsive tissues and that its expression was markedly elevated in the livers of insulin-resistant obese mice. In addition, MKP-3 can activate PEPCK promoter in synergy with dexamethasone in hepatoma cells. Furthermore, ectopic expression of MKP-3 in hepatoma cells by adenoviral infection increased the expression of PEPCK and G6Pase genes and led to elevated glucose production. Taken together, our data strongly suggests that MKP-3 plays a role in regulating gluconeogenic gene expression and hepatic gluconeogenesis. Therefore, dysregulation of MKP-3 expression and/or function in liver may contribute to the pathogenesis of insulin resistance and type II diabetes.
Xu
Haiyan
H
Millennium Pharmaceuticals Incorporated, Cambridge, Massachussetts 02139, USA.
Yang
Qing
Q
Shen
Minhui
M
Huang
Xueming
X
Dembski
Marlene
M
Gimeno
Ruth
R
Tartaglia
Louis A
LA
Kapeller
Rosana
R
Wu
Zhidan
Z
D000256:Adenoviridae / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D054642:Dual Specificity Phosphatase 6; D015971:Gene Expression Regulation, Enzymologic; D015723:Gene Library; D017930:Genes, Reporter; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014018:Tissue Distribution; D014158:Transcription, Genetic
D018076:DNA, Complementary; D007328:Insulin; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D012313:RNA; D003907:Dexamethasone; D000469:Alkaline Phosphatase; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse; C517037:Dusp6 protein, rat; D017027:Protein Tyrosine Phosphatases; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose