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High glucose activates pituitary proopiomelanocortin gene expression: possible role of free radical‐sensitive transcription factors
Author(s) -
Asaba Koichi,
Iwasaki Yasumasa,
Asai Masato,
Yoshida Masanori,
Nigawara Takeshi,
Kambayashi Machiko,
Hashimoto Kozo
Publication year - 2006
Publication title -
diabetes/metabolism research and reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.307
H-Index - 110
eISSN - 1520-7560
pISSN - 1520-7552
DOI - 10.1002/dmrr.677
Subject(s) - proopiomelanocortin , ap 1 transcription factor , promoter , transcription factor , medicine , endocrinology , mediator , transcription (linguistics) , gene , gene expression , chemistry , biology , response element , regulation of gene expression , microbiology and biotechnology , hormone , biochemistry , linguistics , philosophy
Background Hyperglycemia is recognized as a metabolic stress, and indeed it is known to stimulate hypothalamo‐pituitary‐adrenal (HPA) axis, a representative anti‐stress system, in patients with diabetes mellitus or in animal models of hyperglycemia. Thus, we tried to clarify the molecular mechanism of glucose‐induced HPA axis activation. Methods We studied the effect of high glucose on the transcriptional regulation of proopiomelanocortin ( POMC ) gene that encodes adrenocorticotropic hormone, a central mediator of HPA axis, using AtT20 corticotroph cell line in vitro . Results We found that high glucose concentration (24 m M ) significantly stimulated the 5′‐promoter activity of POMC gene. The effect was promoter‐specific, and was mimicked by nuclear factor‐kappaB (NF‐κB)‐ or AP1‐responsive promoters but not by cAMP‐responsive element or serum‐response element‐containing promoters. Furthermore, the stimulatory effect of high glucose on POMC gene was eliminated by NF‐κB and AP1 inhibitors, suggesting the involvement of the transcriptional factors. The POMC 5′‐promoter has the canonical NF‐κB consensus sequence, and gel shift assay showed the binding of NF‐κB to the element. Finally, the effect of high glucose was completely abolished by treatment with a radical quencher 4‐hydroxy‐2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPOL). Conclusions Our data suggest that hyperglycemia activates POMC gene expression, at least partly, via NF‐κB/AP1, and that high‐glucose‐induced free radical generation may mediate the activation of these transcription factors, which in turn stimulates the transcription of POMC gene. Copyright © 2006 John Wiley & Sons, Ltd.