Transcriptional Regulation of Adrenocortical Steroidogenic Gene Expression

Sewer, Marion B.; Dammer, Eric B.; Jagarlapudi, Srinath

doi:10.1080/03602530701498828

Cited by 47 publications

(28 citation statements)

References 114 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A heterodimer of p54 nrb /NONO and paraspeckle protein 1 has been shown to be targeted to paraspeckles in an RNA-dependent manner (15), and p54 nrb /NONO has been shown to be necessary for cyclic AMP (cAMP)-dependent activation of cAMP response element binding protein (CREB) target genes in vivo (16). Finally, the presence of variants of p54 nrb /NONO in human breast cancer (17) and interactions with transcription factors such as PU.1 in erythroleukemia (18) link p54 nrb /NONO to the etiology of pathophysiological processes.Adrenocorticotropin hormone (ACTH) stimulates glucocorticoid biosynthesis by inducing the expression of steroidogenic genes, via a signaling pathway that is mediated by the activation of adenylyl cyclase, increased intracellular cAMP, and the activation of cAMP-dependent protein kinase (PKA) (19,20). We have shown previously that p54 nrb /NONO can regulate the transcription of CYP17A1 (21, 22), a steroidogenic enzyme that functions at a key branch point in biosynthesis of glucocorticoids and adrenal androgens.…”

mentioning

confidence: 99%

p54^nrb/NONO Regulates Cyclic AMP-Dependent Glucocorticoid Production by Modulating Phosphodiesterase mRNA Splicing and Degradation

Lee

Sewer

2015

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

Glucocorticoid production in the adrenal cortex is activated in response to an increase in cyclic AMP (cAMP) signaling. The nuclear protein p54 nrb /NONO belongs to the Drosophila behavior/human splicing (DBHS) family and has been implicated in several nuclear processes, including transcription, splicing, and RNA export. We previously identified p54 nrb /NONO as a component of a protein complex that regulates the transcription of CYP17A1, a gene required for glucocorticoid production. Based on the multiple mechanisms by which p54 nrb /NONO has been shown to control gene expression and the ability of the protein to be recruited to the CYP17A1 promoter, we sought to further define the molecular mechanism by which p54 nrb /NONO confers optimal cortisol production. We show here that silencing p54 nrb /NONO expression in H295R human adrenocortical cells decreases the ability of the cells to increase intracellular cAMP production and subsequent cortisol biosynthesis in response to adrenocorticotropin hormone (ACTH) stimulation. Interestingly, the expression of multiple phosphodiesterase (PDE) isoforms, including PDE2A, PDE3A, PDE3B, PDE4A, PDE4D, and PDE11A, was induced in p54 nrb /NONO knockdown cells. Investigation of the mechanism by which silencing of p54 nrb /NONO led to increased expression of select PDE isoforms revealed that p54 nrb /NONO regulates the splicing of a subset of PDE isoforms. Importantly, we also identify a role for p54 nrb /NONO in regulating the stability of PDE transcripts by facilitating the interaction between the exoribonuclease XRN2 and select PDE transcripts. In summary, we report that p54 nrb /NONO modulates cAMP-dependent signaling, and ultimately cAMP-stimulated glucocorticoid biosynthesis by regulating the splicing and degradation of PDE transcripts. T he non-POU domain-containing octamer-binding protein p54nrb /NONO is a member of the Drosophila behavior/human splicing (DBHS) family of RNA-binding proteins and is comprised of two tandem RNA recognition motif (RRM) domains followed by a charged protein-protein interaction module (1-3). DBHS proteins have been described as multifunctional nuclear proteins, with p54 nrb /NONO being implicated in numerous nuclear processes, including transcription regulation, mRNA splicing, nuclear retention, and subnuclear body formation (4-7). In addition to binding to DNA elements such as intracisternal A particles (8), p54 nrb /NONO is also known to promote the binding of other transcription factors to their response elements (9). The polypyrimidine tract-binding protein-associated splicing factor (PSF)/p54 nrb /NONO heterodimer regulates the transcriptional activity of several nuclear receptors (NRs), including the thyroid hormone receptor (10) and the androgen receptor (11). This heterodimeric complex also promotes nuclear retention of hyperedited RNAs by binding to the inner nuclear matrix structural protein matrin 3 (12, 13) and stimulates topoisomerase I activity (14). A heterodimer of p54 nrb /NONO and paraspeckle protein 1 has been shown to be...

show abstract

mentioning

confidence: 99%

p54^nrb/NONO Regulates Cyclic AMP-Dependent Glucocorticoid Production by Modulating Phosphodiesterase mRNA Splicing and Degradation

Lee

Sewer

2015

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…This is facilitated by a macromolecular complex whose essential component is the steroidogenic acute regulatory protein (STAR; Sewer et al 2007). However, neither the STAR gene nor genes encoding enzymes of the steroid hormone synthesis pathway (present on the microarray: CYP11A1, CYP17A1 and HSD3B2) showed significant differential expression.…”

Section: Results Of the Bioinformatic Analysismentioning

confidence: 99%

“…The most pronounced enrichment showed the biosynthesis of steroids pathway, which participates in cholesterol biosynthesis. Upregulation of the purine metabolism pathway, linked with ATP synthesis, is in line with the stimulation of energy production but may also indicate stimulation of cAMP synthesis, important for ACTH signal transduction (Sewer et al 2007). The importance of the third enriched canonical pathway, N-glycan biosynthesis, is not obvious in the given context.…”

Section: Results Of the Bioinformatic Analysismentioning

confidence: 99%

“…The balance was perhaps shifted towards growth inhibition, as indicated by downregulation of angiotensinogen (AGT), the precursor of angiotensin II, an important factor in the positive regulation of adrenal growth (Huckle & Earp 1994, Vinson 2003. The systemic renin-angiotensin system is the principal activator of aldosterone production in the zona glomerulosa (Sewer et al 2007). However, in addition to its role in aldosterone secretion, the zona glomerulosa is considered to be the site of proliferation, recruitment and differentiation of adrenocortical cell under the control of the locally produced angiotensin II (Vinson 2003).…”

Section: Discussionmentioning

confidence: 99%

“…of miR-202 include CREM (John et al 2004), a transcription factor involved in the regulation of STAR expression and in the transduction of ACTH signalling (Sewer et al 2007). The predominant expression of miR-202 in steroidogenic tissues such as ovary and testis (Ahn et al 2010, Luo et al 2010 provides additional evidence that miR-202 might be involved in the regulation of steroidogenesis.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Differential mRNA expression of genes in the porcine adrenal gland associated with psychosocial stress

Muráni¹,

Ponsuksili²,

D’Eath³

et al. 2011

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

To gain insight into the adrenal stress response, we analysed differential mRNA expression of genes associated with psychosocial stress in the pig (Sus scrofa domestica). Various levels of psychosocial stress were induced by mixing groups of unfamiliar pigs with different aggressiveness. We selected two experimental groups for comparison, each comprising eight animals, which differed significantly in aggressive behaviour and plasma cortisol levels. To identify differentially expressed genes, we compared the adrenal transcriptome of these two groups of pigs, using the Affymetrix GeneChip porcine Genome Array. Bioinformatic analysis revealed that psychosocial stress induced upregulation of transcripts enriched for functions associated with cholesterol accumulation and downregulation of transcripts enriched for functions associated with cell growth and death. These responses are similar to those induced by ACTH stimulation. Nevertheless, the majority of the differentially expressed genes were so far not described as ACTH responsive. Some, such as GAL and GALP, may have responded to sympathoadrenal stimulation. Several of the differentially expressed transcripts, such as AGT, are associated with processes modulating steroidogenic response of adrenocortical cells to ACTH. One of the most significant findings was upregulation of LOC100039095, comprising a precursor of the microRNA miR-202, pointing to a previously unrecognised layer of regulation of adrenal steroidogenesis by microRNA. Our study, performed under entirely physiological conditions, complements previous studies focusing either on a single adrenal tissue and/or on a single stimulus, and contributes to understanding of the fine-tuning of adrenal stress response.

show abstract

Multiple Roles for Sphingolipids in Steroid Hormone Biosynthesis

Lucki

Sewer

Subcellular Biochemistry

Self Cite

View full text Add to dashboard Cite

Steroid hormones are essential regulators of a vast number of physiological processes. The biosynthesis of these chemical messengers occurs in specialized steroidogenic tissues via a multistep process that is catalyzed by members of the cytochrome P450 superfamily of monooxygenases and hydroxysteroid dehydrogenases. Though numerous signaling mediators, including cytokines and growth factors control steroidogenesis, trophic peptide hormones are the primary regulators of steroid hormone production. These peptide hormones activate a cAMP/ cAMP-dependent kinase (PKA) signaling pathway, however, studies have shown that crosstalk between multiple signal transduction pathways and signaling molecules modulates optimal steroidogenic capacity. Sphingolipids such as ceramide, sphingosine, sphingosine-1-phosphate, sphingomyelin, and gangliosides have been shown to control the steroid hormone biosynthetic pathway at multiple levels, including regulating steroidogenic gene expression and activity as well as acting as second messengers in signaling cascades. In this review, we provide an overview of recent studies that have investigated the role of sphingolipids in adrenal, gonadal, and neural steroidogenesis.

show abstract

Transcriptional Regulation of Adrenocortical Steroidogenic Gene Expression

Cited by 47 publications

References 114 publications

p54^nrb/NONO Regulates Cyclic AMP-Dependent Glucocorticoid Production by Modulating Phosphodiesterase mRNA Splicing and Degradation

p54^nrb/NONO Regulates Cyclic AMP-Dependent Glucocorticoid Production by Modulating Phosphodiesterase mRNA Splicing and Degradation

Differential mRNA expression of genes in the porcine adrenal gland associated with psychosocial stress

Multiple Roles for Sphingolipids in Steroid Hormone Biosynthesis

Contact Info

Product

Resources

About

Transcriptional Regulation of Adrenocortical Steroidogenic Gene Expression

Cited by 47 publications

References 114 publications

p54nrb/NONO Regulates Cyclic AMP-Dependent Glucocorticoid Production by Modulating Phosphodiesterase mRNA Splicing and Degradation

p54nrb/NONO Regulates Cyclic AMP-Dependent Glucocorticoid Production by Modulating Phosphodiesterase mRNA Splicing and Degradation

Differential mRNA expression of genes in the porcine adrenal gland associated with psychosocial stress

Multiple Roles for Sphingolipids in Steroid Hormone Biosynthesis

Contact Info

Product

Resources

About

p54^nrb/NONO Regulates Cyclic AMP-Dependent Glucocorticoid Production by Modulating Phosphodiesterase mRNA Splicing and Degradation

p54^nrb/NONO Regulates Cyclic AMP-Dependent Glucocorticoid Production by Modulating Phosphodiesterase mRNA Splicing and Degradation