Regulation of adrenocortical steroid hormone production by RhoA–diaphanous 1 signaling and the cytoskeleton

Sewer, Marion B.; Li, Donghui

doi:10.1016/j.mce.2012.11.014

Cited by 17 publications

(10 citation statements)

References 124 publications

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“…22,23 In addition, the RHOA-ROCK pathway, which acts downstream of ECM-integrin signaling, has been shown to differentially affect steroid hormone production by inhibiting glucocorticoid synthesis and promoting androgen production. 24 Here, we demonstrate that RHOC, another member of the RHO GTPases family, specifically regulates CYP11B2 expression, and presumably aldosterone production, without affecting CYP11B1 or cellular proliferation. Whether RHOC exerts this effect via regulating the actin cytoskeleton or by affecting other signaling pathways requires further research.…”

Section: Discussionmentioning

confidence: 66%

Proteomic Landscape of Aldosterone-Producing Adenoma

et al. 2019

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Primary aldosteronism is a disease of excessive production of adrenal steroid hormones and the most common cause of endocrine hypertension. Primary aldosteronism results mainly from bilateral adrenal hyperplasia or unilateral aldosterone-producing adenoma (APA). Primary aldosteronism cause at the molecular level is incompletely understood and a targeted treatment preventing excessive adrenal steroid production is not available. Here, we perform deep quantitative proteomic and phosphoproteomic profiling of 6 pairs of APA and adjacent nontumoral adrenal cortex. We show that increased steroidogenesis in APA is accompanied by upregulation of steroidogenic enzymes (HSD3B2, CYP21A2, CYP11B2) and of proteins involved in cholesterol uptake (LSR). We demonstrate that HSD3B2 is phosphorylated at Ser95 or 96 and identify a novel phosphorylation site, Ser489, in CYP21A2, suggesting that steroidogenic enzymes are regulated by phosphorylation. Our analysis also reveals altered ECM (extracellular matrix) composition in APA that affects ECM-cell surface interactions and actin cytoskeleton rearrangements. We show that RHOC, a GTPase controlling actin organization in response to extracellular stimuli, is upregulated in APA and promotes expression of the aldosterone synthase gene CYP11B2. Our data also indicate deregulation of protein N-glycosylation and GABAergic signaling in APAs. Finally, we find that mTORC1 (mammalian target of rapamycin complex 1) signaling is the major pathway deregulated in APA. Our study provides a rich resource for future research on the molecular mechanisms of primary aldosteronism.

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Section: Discussionmentioning

confidence: 66%

Proteomic Landscape of Aldosterone-Producing Adenoma

et al. 2019

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“…It has been demonstrated that RhoA participates in regulating secretion of insulin ( 37 ), and is associated with insulin resistance via phosphorylation of insulin receptor substrate-1 ( 38 ). Moreover, it also mediates adrenocorticotropin-stimulated cortisol biosynthesis in human adrenocortical cells ( 39 ). These observations indicate that Regulation of RhoA activity, Signaling by Rho GTPases and RhoA signaling pathways may be associated with PCOS-related hormone imbalance, in particular insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

Pathway and network-based analysis of genome-wide association studies and RT-PCR validation in polycystic ovary syndrome

Shen

Zhou

Zheng

et al. 2017

International Journal of Molecular Medicine

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The purpose of this study was to identify promising candidate genes and pathways in polycystic ovary syndrome (PCOS). Microarray dataset GSE345269 obtained from the Gene Expression Omnibus database includes 7 granulosa cell samples from PCOS patients, and 3 normal granulosa cell samples. Differentially expressed genes (DEGs) were screened between PCOS and normal samples. Pathway enrichment analysis was conducted for DEGs using ClueGO and CluePedia plugin of Cytoscape. A Reactome functional interaction (FI) network of the DEGs was built using ReactomeFIViz, and then network modules were extracted, followed by pathway enrichment analysis for the modules. Expression of DEGs in granulosa cell samples was measured using quantitative RT-PCR. A total of 674 DEGs were retained, which were significantly enriched with inflammation and immune-related pathways. Eight modules were extracted from the Reactome FI network. Pathway enrichment analysis revealed significant pathways of each module: module 0, Regulation of RhoA activity and Signaling by Rho GTPases pathways shared ARHGAP4 and ARHGAP9; module 2, GlycoProtein VI-mediated activation cascade pathway was enriched with RHOG; module 3, Thromboxane A2 receptor signaling, Chemokine signaling pathway, CXCR4-mediated signaling events pathways were enriched with LYN, the hub gene of module 3. Results of RT-PCR confirmed the finding of the bioinformatic analysis that ARHGAP4, ARHGAP9, RHOG and LYN were significantly upregulated in PCOS. RhoA-related pathways, GlycoProtein VI-mediated activation cascade pathway, ARHGAP4, ARHGAP9, RHOG and LYN may be involved in the pathogenesis of PCOS.

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“…In addition, vimentin, one of the cell skeleton proteins, was considered to be the main protein which involved in conveying cholesterol from "cholesterol pool" in cytoplasm to outer membrane of mitochondria [ 11 , 30 ]. In steroidogenic cells, the cholesterol for steroidogenesis is stored in lipid droplets and vimentin intermediate filaments directly contact with mitochondria and lipid droplets [ 12 , 31 , 32 ]. So, vimentin is thought to be a bridge between cholesterol and mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Vimentin-Mediated Steroidogenesis Induced by Phthalate Esters: Involvement of DNA Demethylation and Nuclear Factor κB

Dong

et al. 2016

PLoS ONE

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Di-n-butyl phthalate (DBP) and its active metabolite, monobutyl phthalate (MBP) are the most common endocrine disrupting chemicals. Many studies indicate that high-doses of DBP and/or MBP exhibit toxicity on testicular function, however, little attention have been paid to the effects of low levels of DBP/MBP on steroidogenesis. As we all know, the steroidogenic acute regulatory protein (StAR) is a key regulator involved in the steroidogenesis. Here we found that, in addition to StAR, MBP/DBP increased the steroidogenesis by a cytoskeletal protein, vimentin. Briefly, in murine adrenocortical tumor (Y1) and the mouse Leydig tumor (MLTC-1) cells, vimentin regulated the secretion of progesterone. When these two cells were exposure to MBP, the DNA demethylation in the vimentin promoter was observed. In addition, MBP also induced the activation of nuclear factor kappa B (NF-κB, a transcriptional regulator of vimentin). These two processes improved the transcriptional elevation of vimentin. Knockdown of NF-κB/vimentin signaling blocked the DBP/MBP-induced steroidogenesis. These in vitro results were also confirmed via an in vivo model. By identifying a mechanism whereby DBP/MBP regulates vimentin, our results expand the understanding of the endocrine disrupting potential of phthalate esters.

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Regulation of adrenocortical steroid hormone production by RhoA–diaphanous 1 signaling and the cytoskeleton

Cited by 17 publications

References 124 publications

Proteomic Landscape of Aldosterone-Producing Adenoma

Proteomic Landscape of Aldosterone-Producing Adenoma

Pathway and network-based analysis of genome-wide association studies and RT-PCR validation in polycystic ovary syndrome

Vimentin-Mediated Steroidogenesis Induced by Phthalate Esters: Involvement of DNA Demethylation and Nuclear Factor κB

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