The NGFI-B family of transcription factors regulates expression of 3β-hydroxysteroid dehydrogenase type 2 in the human ovary

Abstract

The nerve growth factor-induced clone B (NGFI-B) family of transcription factors are orphan members of the steroid hormone receptor superfamily. The NGFI-B expression was recently shown in the rat ovarian tissue and appears to be regulated by gonadotrophins. The purpose of our study was to investigate the role of the three members of this family [NGFI-B, Nur-related factor 1 (NURR1) and neuron derived orphan receptor 1 (NOR-1)] in the transcription of genes that encode key steroidogenic enzymes and examine expression in the human ovary. Real-time RT-PCR was used to quantify mRNA expression levels of the NGFI-B family members in human ovarian follicles, corpora lutea and in human granulosa cells after FSH, phorbol ester (TPA) and forskolin treatment. NGFI-B was expressed at higher levels than both NURR1 and NOR-1 in both ovarian follicles and corpora lutea. In human granulosa tumour (HGT) cells, the NGFI-B expression increased after TPA, and to a lesser extent, after forskolin treatment. Treatment of primary cultures of human granulosa cells with forskolin and FSH rapidly increased the NGFI-B mRNA levels followed by an increase in 3beta-hydroxysteroid dehydrogenase type 2 (HSD3B2). Transcription of HSD3B2 was studied by transfecting NGFI-B and steroidogenic factor 1 (SF1) expression vectors with reporter constructs prepared with human steroidogenic acute regulatory protein, cholesterol side-chain cleavage, and HSD3B2 genes. NGFI-B increased the transcription of HSD3B2 in HGT cells which is significantly more than SF1. Mutation or deletion of the NGFI-B response element in the HSD3B2 promoter significantly reduced the NGFI-B-mediated transcription of HSD3B2. Therefore, our data suggest that the NGFI-B may play a significant role in up-regulation of HSD3B2 that leads to the increase in progesterone production that is seen in granulosa cells at ovulation.

Acid Ceramidase (ASAH1) Is a Global Regulator of Steroidogenic Capacity and Adrenocortical Gene Expression

“…6, A and B), both of which regulate CYP21A2 transcription (17,50). Nur77 also modulates StAR gene expression (18). Further, the expression of the transcription factor DAX-1 is significantly down-regulated in ASAH1 KD cells (Fig.…”

Glucocorticoids antagonize cAMP-induced Star transcription in Leydig cells through the orphan nuclear receptor NR4A1

“…NR4A1 binds DNA as a monomer to the sequence AAAAGGTCA, called NR4A1 response element (NBRE), that is very similar to that recognized by the nuclear receptor steroidogenic factor 1 (NR5A1, SF1; Wilson et al 1993), an essential regulator of expression of many steroidogenic genes (reviewed in Parker et al 2002, Val et al 2003. In Leydig cells, NR4A1 has been found to regulate genes involved in steroidogenesis (Zhang & Mellon 1997, Bassett et al 2004, Havelock et al 2005, Martin & Tremblay 2005, including Star (Martin et al 2008).…”

Association of NR4A1 and GNB2L1 genes with reproductive traits in commercial pig breeds

“…Moreover, NR4A1 g.3952A>G may have lower linkage disequilibrium with the causative mutation in this Large White population. The NR4A1 gene is a nuclear steroid hormone receptor and is expressed in the ovarian follicle and ovary (Park et al, 2001) and plays an important role in the regulation of steroid signaling and follicle maturation (Havelock et al, 2005;Li et al, 2010;Dai et al, 2012). It has been reported that increased expression of NR4A1 in pigs under selection for enhanced ovulation rate and embryonic survival may be correlated with an increased sensitivity to steroid hormones in ovarian follicles .…”

“…The gene is rapidly and transiently induced by a luteinizing hormone surge in granulosa cells of preovulatory follicles in rats (Park et al, 2001) and humans (Havelock et al, 2005). The porcine NR4A1 gene is highly expressed in the ovary and uterus (Liu et al, 2011).…”