Regulation of steroidogenesis in transgenic mice and zebrafish

Hu, Meng Chun; Chiang, Evelyn; Tong, Sok-Keng; Lai, W; Hsu, Nai Chi; Wang, Leo Chi Kwang; Chung, Bon Chu

doi:10.1016/s0303-7207(00)00385-3

Cited by 40 publications

(18 citation statements)

References 34 publications

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“…However, we have recently reported that all adrenocortical cells are capable of producing a range of steroids, though the relative production of cortisol, androgens and aldosterone differs (Young et al 2003). The relative production of adrenal steroids is achieved through the differential expression of key steroidogenic enzymes, under the influence of secretagogues (Hu et al 2001). ACTH is the classic secretagogue for both cortisol and adrenal androgens, whereas A-II, though primarily concerned with the production of aldosterone, has also been shown to upregulate cortisol production (Bird et al 1993a, Rainey et al 1993.…”

Section: Discussionmentioning

confidence: 99%

Modulation of steroidogenic enzymes by orphan nuclear transcriptional regulation may control diverse production of cortisol and androgens in the human adrenal

Kelly¹,

McKenna²,

Young³

2004

Journal of Endocrinology

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The capacity of the adrenal to produce cortisol is controlled in part by 21-hydroxylase (CYP21) and the production of androgens by 17-hydroxylase/17-20-lyase (CYP17), in response to secretagogues including ACTH, angiotensin-II (A-II) and insulin. In this study we examined the capacity of human adrenocortical cells to produce cortisol and androgens in response to these secretagogues and their ability to regulate the expression of CYP21 and CYP17. In H-295 cells, forskolin and A-II were found to stimulate production of cortisol relative to androstenedione and a similar pattern of steroid production was noted in primary human adrenocortical cells. Both mRNA and protein expression of CYP21 was upregulated with forskolin and A-II alone and in combination, as detected by Northern and Western blotting. Whereas expression of CYP17 mRNA and protein was upregulated in the presence of forskolin and forskolin in combination with insulin. The ability of steroidogenic factor-1 (SF-1) and nur77 to regulate transcription of these enzymes was examined. Forskolin, A-II and insulin increased the protein expression of SF-1. Increased binding of SF-1 to its response element in the presence of forskolin, A-II and insulin was observed. Nur77 was expressed primarily in the zona glomerulosa and fasciculata. Increased protein expression of nur77 and the greatest binding of nur77 to its response element was seen when cells were stimulated with A-II in combination with forskolin. These data indicate that nur77 may preferentially regulate steroid enzyme genes relevant to cortisol production and thereby regulate differential cortisol and adrenal androgen production.

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Section: Discussionmentioning

confidence: 99%

Modulation of steroidogenic enzymes by orphan nuclear transcriptional regulation may control diverse production of cortisol and androgens in the human adrenal

Kelly¹,

McKenna²,

Young³

2004

Journal of Endocrinology

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“…Effects of trophic hormones are mediated via second messengers and changes in the expression of specific enzymes and transcription factors (Hanukoglu, 1992;Waterman and Bischof, 1996;Cooke, 1999;Hu et al, 2001). The list of trophic hormone-induced genes includes genes that encode diverse steroidogenic enzymes, regulatory proteins and mitochondrial genes that are involved in energy production (Viard et al, 1992;Raikhinstein and Hanukoglu, 1993;Lehoux et al, 1998;Wood and Strauss, 2002).…”

Section: Introductionmentioning

confidence: 99%

ACTH induces TIMP-1 expression and inhibits collagenase in adrenal cortex cells

Reichenstein

Reich

Lehoux

et al. 2004

Molecular and Cellular Endocrinology

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To identify genes that are induced by corticotropin (ACTH) in adrenal cortex cells, we carried out a differential hybridization screening of adrenal cortex cDNA libraries. Some of the clones we identified represented tissue inhibitor of metalloproteinase 1 (TIMP-1) mRNA. We examined ACTH dependence of the expression of TIMP-1 in vitro in cultured bovine adrenocortical cells, and in ACTH-treated rats. Northern blot analysis of total RNA from cells showed that the level of TIMP-1 mRNA increases sharply within 3 h after ACTH stimulation. Since TIMP-1 inhibits some cell matrix metalloproteinases (MMPs) of the collagenase type, we examined the effect of ACTH on collagenase activity in bovine adrenocortical cells. Exposure of confluent cultures to ACTH for 24 h showed dose-dependent inhibition of collagenase activity. Northern blot analysis of total RNA from rat adrenal zona fasciculata-reticularis and zona glomerulosa showed that in both of these zones TIMP-1 expression was induced within 12 h after ACTH injection. Long-term (9 days) treatment with ACTH increased TIMP-1 mRNA levels nearly sixfold in zona fasciculata-reticularis. Overall, our results show that ACTH causes induction of TIMP-1 and suppression of collagenase activity, and suggest that ACTH may modulate the activities of MMPs and hence cell matrix remodeling.

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“…In adrenocortical cells, activation of the cAMP-PKA pathway increases the expression of several SF-1-regulated steroidogenic genes (5,20,29,41), including Cyp11a1, which encodes cytochrome P450scc, catalyzing the first and rate-limiting step of steroidogenesis. However, the mechanism by which the cAMP-PKA pathway activates SF-1-mediated transcription is still elusive.…”

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confidence: 99%

SF-1 (Nuclear Receptor 5A1) Activity Is Activated by Cyclic AMP via p300-Mediated Recruitment to Active Foci, Acetylation, and Increased DNA Binding

Chen

Juan

Chung

2005

Molecular and Cellular Biology

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Steroidogenic factor 1 (SF-1) is a nuclear receptor essential for steroidogenic gene expression, but how its activity is regulated is unclear. Here we demonstrate that p300 plays an important role in regulating SF-1 function. SF-1 was acetylated in vitro and in vivo by p300 at the KQQKK motif in the Ftz-F1 (Fushi-tarazu factor 1) box adjacent to its DNA-binding domain. Mutation of the KQQKK motif reduced the DNA-binding activity and p300-dependent activation of SF-1. When stimulated with cyclic AMP (cAMP), adrenocortical Y1 cells expressed more p300, leading to additional SF-1 association with p300 and increased SF-1 acetylation and DNA binding. It also increased SF-1 colocalization with p300 in nuclear foci. Collectively, these results indicate that SF-1 transcriptional activity is regulated by p300 in response to the cAMP signaling pathway by way of increased acetylation, DNA binding, and recruitment to nuclear foci.Steroidogenic factor 1 (SF-1), also known as Ad4BP (adrenal 4 binding protein), is a member of the nuclear receptor superfamily, designated NR5A1 (39). SF-1 plays a critical role in the development, differentiation, and function of the hypothalamus, pituitary, adrenal glands, and gonads (43). SF-1 controls the expression of a variety of genes, such as steroidogenic genes, Müllerian inhibitory substance, and the ␣-subunit and ␤-subunit of gonadotropins (37, 43). SF-1 exerts its transcriptional activity through interaction with numerous proteins, including coactivators, corepressors, and other transcription factors (2, 9-11, 24, 35, 36, 42). SF-1 is structurally similar to steroid receptors; it contains a zinc finger DNA-binding domain (DBD) and a C-terminal ligand-binding domain but lacks the N-terminal A/B domain (Fig. 1A). Members of the nuclear receptor 5 (NR5) subfamily, including Drosophila melanogaster FTZ-F1 (NR5A3), silkworm BmFTZ-F1, and mammalian LRH-1 (liver receptor homologue 1) (NR5A2) and SF-1 (NR5A1), share a conserved 30-amino-acid (aa) basic region, designated the Ftz-F1 (Fushitarazu factor 1) box, adjacent to the C terminus of the DNAbinding domain (52). This box facilitates recognition of the first three bases of the DNA sequence PyCAAGGPyCPu (52). The Ftz-F1 box together with its adjacent proline-rich sequence (aa 78 to 172), called the FP domain, is important for the transactivation function of SF-1 (30). It is also important for nuclear localization as well as interaction with TFIIB and c-Jun (30).SF-1 is modified by phosphorylation and SUMO conjugation at the hinge domain. The phosphorylation site is mediated by mitogen-activated protein kinase and required for maximal transcriptional activity of SF-1 (17). SUMO conjugation represses SF-1 activity by recruiting transcriptional repressors like DP103 and/or by relocating SF-1 to nuclear speckles (7,26,28).In addition to phosphorylation and SUMO conjugation, SF-1 is also acetylated (25). Two well-characterized histone acetyltransferase (HAT) proteins are in the p300/CBP (CREBbinding protein) family and the PCAF/GCN5 (p300/CBP-ass...

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Regulation of steroidogenesis in transgenic mice and zebrafish

Cited by 40 publications

References 34 publications

Modulation of steroidogenic enzymes by orphan nuclear transcriptional regulation may control diverse production of cortisol and androgens in the human adrenal

Modulation of steroidogenic enzymes by orphan nuclear transcriptional regulation may control diverse production of cortisol and androgens in the human adrenal

ACTH induces TIMP-1 expression and inhibits collagenase in adrenal cortex cells

SF-1 (Nuclear Receptor 5A1) Activity Is Activated by Cyclic AMP via p300-Mediated Recruitment to Active Foci, Acetylation, and Increased DNA Binding

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