Protein kinase CK2 down-regulates glucose-activated expression of the acetyl-CoA carboxylase gene.
It has been suggested that, in pancreatic beta-cells, acetyl-CoA carboxylase (ACC) is a key enzyme in glucose signal transduction leading to glucose-induced insulin secretion. The PII promoter is the only active promoter for the ACC gene in the beta-cell. Here we report that, in the pancreatic beta-cell, high glucose levels (above 20 mm) activate Sp1 binding to the glucose response element of the PII promoter, which leads to a dose-dependent increase in PII transcription. The expression of a gene coding protein kinase CK2 (CK2) alpha subunit, or the presence of okadaic acid (a serine/threonine protein phosphatase inhibitor), partially blocks the glucose activation of PII transcription. The inhibitory effect of CK2 alpha, or okadaic acid, was not observed in the absence of glucose or at low glucose concentrations. Phosphorylation of Sp1 by CK2 alpha leads to the inactivation of Sp1 binding to PII. Dephosphorylation of the phosphorylated Sp1 by protein phosphatase 1 (PP1) activates the binding of Sp1 to PII. Inhibition of PP1-catalyzed Sp1 dephosphorylation by okadaic acid, or PP1 specific inhibitor 2, decreases Sp1 binding to PII. These results suggest that the phosphorylation/dephosphorylation of Sp1 by CK2/PP1 may be the underlying mechanism by which the expression of the PII promoter of ACC is controlled in the process of glucose-mediated insulin secretion in pancreatic beta-cells.
Zhang
S
S
Department of Biochemistry, Purdue University, West Lafayette, Indiana, 47907, USA.
Kim
K H
KH
D000103:Acetyl-CoA Carboxylase / Q000235:genetics*; D000818:Animals; D047390:Casein Kinase II; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000502:physiology*; D007515:Islets of Langerhans / Q000201:enzymology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D016329:Sp1 Transcription Factor / Q000502:physiology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D016329:Sp1 Transcription Factor; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D000103:Acetyl-CoA Carboxylase; D005947:Glucose