Interaction of pituitary hormones and expression of clock genes modulated by bone morphogenetic protein-4 and melatonin.
Functional interaction of clock genes and pituitary hormones was investigated by focusing on bone morphogenetic protein (BMP)-4 and melatonin actions in anterior pituitary cells. A significant correlation between the mRNA expression of proopiomelanocortin (POMC) and Per2 was revealed in serial cultures of corticotrope AtT20 cells. Knockdown of Per2 expression by siRNA in AtT20 cells resulted in a significant reduction of POMC mRNA level with or without corticotropin-releasing hormone (CRH) stimulation. Treatments with BMP-4 and melatonin, both of which suppress POMC expression, reduced Per2 mRNA as well as protein levels in AtT20 cells. On the other hand, in lactosomatotrope GH3 cells, an expressional correlation was found between prolactin (PRL) and Clock mRNA levels, which was attenuated in the presence of forskolin treatment. The siRNA-mediated knockdown of Clock expression, but not that of Bmal1, significantly reduced PRL mRNA levels in GH3 cells. Interestingly, Clock mRNA and protein levels did not fluctuate with melatonin, BMP-4 or forskolin treatment, although Bmal1 expression was significantly increased by forskolin treatment. Collectively, a significant correlation between the expression of POMC and Per2 and that between PRL and Clock were uncovered in corticotrope and lactosomatotrope cells, respectively. Per2 expression was inhibited by POMC modulators including melatonin and BMP-4, while Clock expression was steadily maintained. Thus, the effects of melatonin and BMP-4 on clock gene expression may imply differential stability of circadian rhythms of adrenocorticotropin (ACTH) and PRL secreted from the anterior pituitary.
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
Naoko
N
Tsukamoto-Yamauchi
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
Tomohiro
T
Terasaka
Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan.
Yasumasa
Y
Iwasaki
Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan. Electronic address: fumiotsu@md.okayama-u.ac.jp.
Fumio
F
Otsuka
D056930:ARNTL Transcription Factors / Q000235:genetics; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology* / Q000502:physiology; D056926:CLOCK Proteins / Q000235:genetics; D002460:Cell Line / Q000187:drug effects; D057906:Circadian Clocks / Q000187:drug effects / Q000235:genetics*; D052680:Corticotrophs / Q000187:drug effects / Q000502:physiology*; D056931:Cryptochromes / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D052682:Lactotrophs / Q000187:drug effects / Q000502:physiology; D008550:Melatonin / Q000494:pharmacology* / Q000502:physiology; D051379:Mice; D056950:Period Circadian Proteins / Q000235:genetics; D011333:Pro-Opiomelanocortin / Q000235:genetics; D011388:Prolactin / Q000235:genetics / Q000378:metabolism; D051381:Rats
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D055415:Bone Morphogenetic Protein 4; D056931:Cryptochromes; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D011333:Pro-Opiomelanocortin; D011388:Prolactin; D056926:CLOCK Proteins; C538944:Clock protein, mouse; D008550:Melatonin
Bone morphogenetic protein (BMP); Melatonin; Pituitary cells; Prolactin (PRL); Proopiomelanocortin (POMC)