Transcriptional mechanism of suppression of insulin gene expression by AMP-activated protein kinase activator 5-amino-4-imidazolecarboxamide riboside (AICAR) in beta-cells.
It is well known that the activation of AMP-activated protein kinase (AMPK) represses insulin gene expression and glucose-stimulated insulin secretion. However, how this effect is achieved and the effects of AMPK activation on glucolipotoxicity-induced beta-cell dysfunction have not been elucidated. We investigate whether BETA2 gene expression are involved in the AMPK-mediated regulation of insulin gene expression in normal and dysfunctional beta-cells. BETA2 gene expression and protein levels were significantly decreased by AICAR treatment and those were associated with the suppression of BETA2 promoter activity and DNA binding activity. These results demonstrate that the expressions of BETA2 and insulin gene are positively regulated by glucose and negatively by AMPK. Therefore, AMPK may function as a key molecule, which conveys extracellular metabolic signals into the cells and finely tunes expression of beta-cell specific transcription factors in response to glucose level.
Kim
Ji-Won
JW
Department of Endocrinology and Metabolism, The Catholic University of Korea, 505, Ban-po-Dong, Seocho-Gu, Seoul 137-090, Republic of Korea.
Cho
Jae-Hyoung
JH
Ko
Seung-Hyun
SH
Park
Heon-Seok
HS
Ha
Joohun
J
Song
Ki-Ho
KH
Son
Ho-Young
HY
Kim
Sung-Soo
SS
Yoon
Kun-Ho
KH
Suh-Kim
Haeyoung
H
D000091162:AMP-Activated Protein Kinase Kinases; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D012265:Ribonucleotides / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
D007328:Insulin; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; C031143:AICA ribonucleotide