Glucocorticoid receptor mediated repression of human insulin gene expression is regulated by PGC-1alpha.
Transcriptional regulation of the insulin gene plays a critical role in maintenance of pancreatic beta cell function in response to various stimuli. Here, we used INS-1 cells to test the hypothesis that PGC-1alpha regulates human insulin gene transcription by modulating glucocorticoid (GR) binding to the insulin gene promoter. Analysis of the human insulin promoter region revealed that the suppressive region regulated by GR and PGC-1alpha is localized from -362 to -257 bp. To locate the GR binding site in the human insulin promoter region, EMSAs were performed with candidate GR binding sequences and confirmed that a palindromic region (Palin, -284 to -274 bp) specifically interacts with GR. We also found that the Palin-binding activity of GR is increased in the presence of PGC-1alpha. These findings suggest that PGC-1alpha elevates the binding of GR to Palin and thereby enhances the GR-mediated inhibition of human insulin transcription.
Jang
Won Gu
WG
Department of Genetic Engineering, Kyungpook National University, Daegu, Republic of Korea.
Kim
Eun Jung
EJ
Park
Keun-Gyu
KG
Park
Yong Bok
YB
Choi
Hueng-Sik
HS
Kim
Hye-Jin
HJ
Kim
Yong Deuk
YD
Kim
Kyung-Sup
KS
Lee
Ki-Up
KU
Lee
In-Kyu
IK
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors