title: Retinoic acid receptor-α up-regulates proopiomelanocortin gene expression in AtT20 corticotroph cells.
abstract: Cushing's disease is a disorder caused by excessive ACTH secretion from a corticotroph tumor of the pituitary gland. Although its standard therapy is a transsphenoidal surgery, innovation of novel medical treatments for the disease is urgently necessary. Retinoic acid (RA) has been reported to suppress adrenocorticotropic hormone (ACTH) secretion in Cushing's disease. However, the role of RA receptor (RAR) in proopiomelanocortin (Pomc) gene expression remains uncertain. We here examined the involvement of RARα in Pomc regulation using AtT20 corticotroph cells. Surprisingly, a synthetic RARα agonist Am80 increased Pomc mRNA expression, CRH-induced ACTH secretion, and Pomc promoter activity. Small interfering RNA-mediated RARα-knockdown suppressed both basal and Am80-induced Pomc promoter activity. RARα-overexpression dose-dependently increased Pomc promoter activity. Pomc promoter mutation analysis revealed that both Tpit and NeuroD1 binding elements were responsible for the Am80-mediated effect. Am80 increased Tpit expression while RAR antagonist LE540 suppressed the increase. Tpit-overexpression increased Pomc promoter activity. Mammalian two-hybrid assay revealed that Am80 induced NeuroD1-RARα interaction. NeuroD1-overexpression enhanced the Am80-induced Pomc promoter activity, which was suppressed by NeuroD1 truncated mutant-overexpression. RARα thus positively regulates ACTH secretion/Pomc gene expression through interaction with NeuroD1 and Tpit expression increase. The present observation will be useful for the future development of the RA/retinoid-derived therapeutics of the disease.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Uruno
authors.forename: Akiko
authors.initials: A
authors.lastname: Saito-Hakoda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yokoyama
authors.forename: Naotaka
authors.initials: N
authors.lastname: Kogure
authors.forename: Ken
authors.initials: K
authors.lastname: Matsuda
authors.forename: Rehana
authors.initials: R
authors.lastname: Parvin
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shimizu
authors.forename: Ikuko
authors.initials: I
authors.lastname: Sato
authors.forename: Masataka
authors.initials: M
authors.lastname: Kudo
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Sadayoshi
authors.initials: S
authors.lastname: Ito
authors.forename: Akira
authors.initials: A
authors.lastname: Sugawara
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D045744:Cell Line, Tumor; D051379:Mice; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis*; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
chemical_list: D001565:Benzoates; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D013764:Tetrahydronaphthalenes; C061133:tamibarotene; D011333:Pro-Opiomelanocortin