Regulation of NGFI-B/Nur77 gene expression in the rat ovary and in leydig tumor cells MA-10.
NR4A1, also called NGFI-B in the rat, Nur77 in the mouse and TR3 in humans, belongs to the orphan nuclear steroid hormone receptor superfamily and is one of the immediate-early genes. In the endocrine organs, including the gonads, NGFI-B/Nur77 gene expression is rapidly induced by pituitary hormones. NGFI-B/Nur77 expression was found to be rapidly reduced by an estrogenic endocrine disrupter, diethylstilbestrol (DES) in theca interna cells of immature rat ovaries. DES treatment also triggered a rapid decrease of serum luteinizing hormone (LH) levels, suggesting that DES acts on the hypothalamo-pituitary axis to suppress LH secretion from the pituitary. The transcriptional regulation of NGFI-B/Nur77 by LH/human chorionic gonadotropin (hCG) or 8-bromoadenosine 3'-5'-cyclic monophosphate (8 Br-cAMP) was examined in mouse Leydig tumor cells MA-10. Luciferase assays using NGFI-B/Nur77 promoter constructs and electric mobility shift assays (EMSA) showed that NGFI-B/Nur77 gene expression was mediated through three of the four activator protein-1 (AP-1)-like sites, namely the -233 AP-1, -213 AP-1 and -69 AP-1 sites adjacent to the transcription start site of the NGFI-B/Nur77 promoter. We also demonstrated here that both the Jun family and cAMP-responsive element binding (CREB) proteins bind to the -233 AP-1 site, whereas the main binding protein to the -213 AP-1 site was CREB, and Jun family protein to the -69 AP-1 site, respectively. The rapid induction of NGFI-B/Nur77 gene expression by LH/hCG in MA-10 cells appears to be mediated by both CREB and Jun family proteins through the cAMP-protein kinase A (PKA) pathway.
Inaoka
Yoshihiko
Y
Department of Biochemistry, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Yazawa
Takashi
T
Uesaka
Miki
M
Mizutani
Tetsuya
T
Yamada
Kazuya
K
Miyamoto
Kaoru
K
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004054:Diethylstilbestrol / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D007984:Leydig Cell Tumor / Q000378:metabolism* / Q000473:pathology; D007986:Luteinizing Hormone / Q000494:pharmacology; D051379:Mice; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D011987:Receptors, Steroid / Q000096:biosynthesis*; D020218:Response Elements; D013799:Theca Cells / Q000378:metabolism* / Q000473:pathology; D018808:Transcription Factor AP-1
D006063:Chorionic Gonadotropin; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D004968:Estrogens, Non-Steroidal; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016755:Proto-Oncogene Proteins c-jun; D011987:Receptors, Steroid; D018808:Transcription Factor AP-1; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004054:Diethylstilbestrol; D007986:Luteinizing Hormone; D017868:Cyclic AMP-Dependent Protein Kinases