Rasd1 Modulates the Coactivator Function of NonO in the Cyclic AMP Pathway

Ong, Shufen Angeline; Tan, Jen Jen; Tew, Wai Loon; Chen, Ken-Shiung

doi:10.1371/journal.pone.0024401

Cited by 15 publications

(12 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…p54 nrb /NONO was also shown to be involved in a multiprotein complex with SF1, PSF, LRH1, and high-mobility group proteins that regulate cAMP-stimulated retinol-binding protein transcription (39). In addition, p54 nrb /NONO can bind to Rasd1 to regulate the cAMP signaling cascade (40). In this study, we identified p54 nrb /NONO as a novel regulator of PDE expression by controlling the degradation of select PDE isoforms.…”

Section: Discussionmentioning

confidence: 84%

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

Lee

Sewer

2015

Molecular and Cellular Biology

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

Section: Discussionmentioning

confidence: 84%

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

Lee

Sewer

2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…This results in inhibition of the cAMP-PKA-CREB signaling pathway and so forms a possible feedback mechanism for regulation of MCN and PCNs. There is also in vitro evidence from reporter assays that Rasd1 acts at cAMP response element (CRE) sites within target gene promoters, to directly inhibit transcription [ 26 , 27 ]. Thus, Rasd1 has the capacity to influence transcriptional events either indirectly, by inhibiting AC activity at the cell membrane, or directly, through modulation of activity at the level of the promoter.…”

Section: Introductionmentioning

confidence: 99%

Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation

et al. 2016

View full text Add to dashboard Cite

BackgroundRasd1 is a member of the Ras family of monomeric G proteins that was first identified as a dexamethasone inducible gene in the pituitary corticotroph cell line AtT20. Using microarrays we previously identified increased Rasd1 mRNA expression in the rat supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus in response to increased plasma osmolality provoked by fluid deprivation and salt loading. RASD1 has been shown to inhibit adenylyl cyclase activity in vitro resulting in the inhibition of the cAMP-PKA-CREB signaling pathway. Therefore, we tested the hypothesis that RASD1 may inhibit cAMP stimulated gene expression in the brain.ResultsWe show that Rasd1 is expressed in vasopressin neurons of the PVN and SON, within which mRNA levels are induced by hyperosmotic cues. Dexamethasone treatment of AtT20 cells decreased forskolin stimulation of c-Fos, Nr4a1 and phosphorylated CREB expression, effects that were mimicked by overexpression of Rasd1, and inhibited by knockdown of Rasd1. These effects were dependent upon isoprenylation, as both farnesyltransferase inhibitor FTI-277 and CAAX box deletion prevented Rasd1 inhibition of cAMP-induced gene expression. Injection of lentiviral vector into rat SON expressing Rasd1 diminished, whereas CAAX mutant increased, cAMP inducible genes in response to osmotic stress.ConclusionsWe have identified two mechanisms of Rasd1 induction in the hypothalamus, one by elevated glucocorticoids in response to stress, and one in response to increased plasma osmolality resulting from osmotic stress. We propose that the abundance of RASD1 in vasopressin expressing neurons, based on its inhibitory actions on CREB phosphorylation, is an important mechanism for controlling the transcriptional responses to stressors in both the PVN and SON. These effects likely occur through modulation of cAMP-PKA-CREB signaling pathway in the brain.

show abstract

“…5,6 The activation of TRPC channels involves Ga q/11 proteins and PLC. Molecules downstream of PLC, such as IP 3 and DAG, and PIP 2 hydrolysis have been suggested as activators and as an activation mechanism for TRPC channels, respectively.…”

Section: Trpc4 Channelsmentioning

confidence: 99%

The Roles of Rasd1 small G proteins and leptin in the activation of TRPC4 transient receptor potential channels

et al. 2015

View full text Add to dashboard Cite

#These authors contributed equally to this work TRPC4 is important regulators of electrical excitability in gastrointestinal myocytes, pancreatic b-cells and neurons. Much is known regarding the assembly and function of these channels including TRPC1 as a homotetramer or a heteromultimer and the roles that their interacting proteins play in controlling these events. Further, they are one of the best-studied targets of G protein-coupled receptors and growth factors in general and Ga i/o and Ga q protein coupled receptor or epidermal growth factor and leptin in particular. However, our understanding of the roles of small G proteins and leptin on TRPC4 channels is still rudimentary. We discuss potential roles for Rasd1 small G protein and leptin in channel activation in addition to their known role in cellular signaling.

show abstract

Rasd1 Modulates the Coactivator Function of NonO in the Cyclic AMP Pathway

Cited by 15 publications

References 85 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

Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation

The Roles of Rasd1 small G proteins and leptin in the activation of TRPC4 transient receptor potential channels

Contact Info

Product

Resources

About

Rasd1 Modulates the Coactivator Function of NonO in the Cyclic AMP Pathway

Cited by 15 publications

References 85 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

Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation

The Roles of Rasd1 small G proteins and leptin in the activation of TRPC4 transient receptor potential channels

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