The role of microRNAs in glucocorticoid action

Clayton, Sally A.; Jones, Simon W.; Kurowska‐Stolarska, Mariola; Clark, Andrew R.

doi:10.1074/jbc.r117.000366

Cited by 62 publications

(46 citation statements)

References 98 publications

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“…MicroRNAs (miRNAs) have been reported to be implicated in many cell functions, such as proliferation, differentiation, development, and apoptosis . miRNAs are differentially expressed during the course of liver fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Long noncoding RNA HOTTIP mediates SRF expression through sponging miR‐150 in hepatic stellate cells

Zheng

Mao

Dong

et al. 2018

J Cellular Molecular Medi

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HOXA transcript at the distal tip (HOTTIP) has been shown to be up‐regulated in a variety of cancers and is identified as an oncogenic long noncoding RNA. However, the biological role of HOTTIP in liver fibrosis is unclear. Here, we reported that HOTTIP was specifically overexpressed in activated hepatic stellate cells (HSCs). HOTTIP knockdown suppressed the activation and proliferation of HSCs. Luciferase reporter assay showed that HOTTIP and serum response factor (SRF) were targets of miR‐150. RNA binding protein immunoprecipitation assay indicated the interaction between miR‐150 and HOTTIP. Further study revealed that HOTTIP increased SRF expression as a competing endogenous RNA for miR‐150, thus prompting HSC activation. Taken together, we provide a novel HOTTIP‐miR‐150‐SRF signalling cascade in liver fibrosis.

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Section: Introductionmentioning

confidence: 99%

Long noncoding RNA HOTTIP mediates SRF expression through sponging miR‐150 in hepatic stellate cells

Zheng

Mao

Dong

et al. 2018

J Cellular Molecular Medi

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“…can be induced by endogenous and exogenous glucocorticoids (Clayton et al, 2018). In summary, CS induces the expression of a regulator (miR-124) that mediates the destabilization of a primary gene (Ptbp1), secondary to the enhancement of Ptbp1 mRNA by CS.…”

Section: Discussionmentioning

confidence: 99%

“…4A). Of emerging interest is the role of miRNAs as mediators of glucocorticoid signaling and response (Clayton et al, 2018). On the basis of this analysis, 20 genes were found to interact with at least one miRNA in murine or rodent models.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the CS cause homologous downregulation of their own receptors via decreased transcription. Growing evidence indicates that CS modulate many transcription factors such as CCAAT-enhancer binding protein (C/EBP) and hepatocyte nuclear factor-1a (HNF-1a), as well as miRNAs (Suh and Rechler, 1997;Phuc Le et al, 2005;Smith et al, 2013;Clayton et al, 2018). The altered expression of these transcription factors and miRNAs can in turn affect the expression of other genes during transcriptional and translational processing of mRNA and peptides (Valinezhad Orang et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

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Modeling Corticosteroid Pharmacogenomics and Proteomics in Rat Liver

Ayyar

Sukumaran

DuBois

et al. 2018

J Pharmacol Exp Ther

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Corticosteroids (CS) regulate the expression of numerous genes at the mRNA and protein levels. The time course of CS pharmacogenomics and proteomics were examined in livers obtained from adrenalectomized rats given a 50-mg/kg bolus dose of methylprednisolone. Microarrays and mass spectrometry-based proteomics were employed to quantify hepatic transcript and protein dynamics. One-hundred, sixty-three differentially expressed mRNA and their corresponding proteins (163 genes) were clustered into two dominant groups. The temporal profiles of most proteins were delayed compared with their mRNA, attributable to synthesis delays and slower degradation kinetics. On the basis of our fifth-generation model of CS, mathematical models were developed to simultaneously describe the emergent time patterns for an array of steroid-responsive mRNA and proteins. The majority of genes showed time-dependent increases in mRNA and protein expression before returning to baseline. A model assuming direct, steroid-mediated stimulation of mRNA synthesis was applied. Some mRNAs and their proteins displayed down-regulation following CS. A model assuming receptor-mediated inhibition of mRNA synthesis was used. More complex patterns were observed for other genes (e.g., biphasic behaviors and opposite directionality in mRNA and protein). Models assuming either stimulation or inhibition of mRNA synthesis coupled with dual secondarily induced regulatory mechanisms affecting mRNA or protein turnover were derived. These findings indicate that CS-regulated gene expression manifested at the mRNA and protein levels are controlled via mechanisms affecting key turnover processes. Our quantitative models of CS pharmacogenomics were expanded from mRNA to proteins and provide extended hypotheses for understanding the direct, secondary, and downstream mechanisms of CS actions.

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“…MicroRNAs (miRNAs), a subclass of noncoding RNAs, make an interesting candidate for the regulation of GR because they are potent inhibitors of post‐transcriptional gene expression via target cleavage or translational repression (10). Although studies have described GC‐regulated miRNAs that modulate liver and systemic metabolism (1), as well as miRNAs that target the GR in the brain and in the context of different types of cancer (11), there is a dearth of investigation into miRNAs' involvement in regulating the GC‐GR axis itself in peripheral and metabolic tissues and their potential contribution to GC resistance.…”

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confidence: 99%

A miR‐29a‐driven negative feedback loop regulates peripheral glucocorticoid receptor signaling

et al. 2019

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The glucocorticoid receptor (GR) represents the crucial molecular mediator of key endocrine, glucocorticoid hormone–dependent regulatory circuits, including control of glucose, protein, and lipid homeostasis. Consequently, aberrant glucocorticoid signaling is linked to severe metabolic disorders, including insulin resistance, obesity, and hyperglycemia, all of which also appear upon chronic glucocorticoid therapy for the treatment of inflammatory conditions. Of note, long‐term glucocorticoid exposure under these therapeutic conditions typically induces glucocorticoid resistance, requiring higher doses and consequently triggering more severe metabolic phenotypes. However, the molecular basis of acquired glucocorticoid resistance remains unknown. In a screen of differential microRNA expression during glucocorticoid‐dependent adipogenic differentiation of human multipotent adipose stem cells, we identified microRNA 29a (miR‐29a) as one of the most down‐regulated transcripts. Over‐expression of miR‐29a impaired adipogenesis. We found that miR‐29a represses GR in human adipogenesis by directly targeting its mRNA, and downstream analyses revealed that GR mediates most of miR‐29a's anti‐adipogenic effects. Conversely, miR‐29a expression depends on GR activation, creating a novel miR‐29‐driven feedback loop. miR‐29a and GR expression were inversely correlated both in murine adipose tissue and in adipose tissue samples obtained from human patients. In the latter, miR‐29a levels were additionally strongly negatively correlated with body mass index and adipocyte size. Importantly, inhibition of miR‐29 in mice partially rescued the down‐regulation of GR during dexamethasone treatment. We discovered that, in addition to modulating GR function under physiologic conditions, pharmacologic glucocorticoid application in inflammatory disease also induced miR‐29a expression, correlating with reduced GR levels. This effect was abolished in mice with impaired GR function. In summary, we uncovered a novel GR‐miR‐29a negative feedback loop conserved between mice and humans, in health and disease. For the first time, we elucidate a microRNA‐related mechanism that might contribute to GR dysregulation and resistance in peripheral tissues.—Glantschnig, C, Koenen, M., Gil‐Lozano, M., Karbiener, M., Pickrahn, I., Williams‐Dautovich, J., Patel, R., Cummins, C. L., Giroud, M., Hartleben, G., Vogl, E., Blüher, M., Tuckermann, J., Uhlenhaut, H., Herzig, S., Scheideier, M. A. miR‐29a–driven negative feedback loop regulates peripheral glucocorticoid receptor signaling. FASEB J. 33, 5924–5941 (2019). http://www.fasebj.org

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The role of microRNAs in glucocorticoid action

Cited by 62 publications

References 98 publications

Long noncoding RNA HOTTIP mediates SRF expression through sponging miR‐150 in hepatic stellate cells

Long noncoding RNA HOTTIP mediates SRF expression through sponging miR‐150 in hepatic stellate cells

Modeling Corticosteroid Pharmacogenomics and Proteomics in Rat Liver

A miR‐29a‐driven negative feedback loop regulates peripheral glucocorticoid receptor signaling

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