HuR-Dependent Editing of a New Mineralocorticoid Receptor Splice Variant Reveals an Osmoregulatory Loop for Sodium Homeostasis

Lema, Ingrid; Amazit, Larbi; Lamribet, Khadija; Fagart, Jérôme; Blanchard, Anne; Lombès, Marc; Cherradi, Nadia; Viengchareun, Say

doi:10.1038/s41598-017-04838-8

Cited by 8 publications

(4 citation statements)

References 47 publications

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“…It is believed that chronic activation/cytoplasmic localization of HuR can facilitate the etiology of certain diseases by causing aberrant mRNA expression changes associated with inflammation (Srikantan & Gorospe, ). In normal cells, HuR principally resides in the nucleus where it can effect splicing (Akaike et al, ; Chang et al, ; Gauchotte et al, ; Izquierdo, , ; Lebedeva et al, ; Lema et al, ; Srikantan & Gorospe, ) and alternative polyadenylation (Dutertre et al, ) of targets. Chronic activation and cytoplasmic localization of HuR; however, can lead to a strong proinflammatory response governed by HuR's stabilization of proinflammatory cytokines such as IL‐6, IL‐8, TGF‐β, TNF‐α, IFN‐γ, CCR6, proinflammatory enzymes COX‐2, and iNOS (J. Chen et al, ; Di Marco et al, ; Gurgis et al, ; Matsye et al, ; Nabors et al, ; Shin et al, ; J. G. Wang et al, ; H. Zhou et al, ), and the inflammatory marker CRP (Y. Kim et al, ) among others.…”

Section: Hur's Role In the Pathobiology Of Diseasementioning

confidence: 99%

Understanding and targeting the disease‐related RNA binding protein human antigen R (HuR)

et al. 2020

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Altered gene expression is a characteristic feature of many disease states such as tumorigenesis, and in most cancers, it facilitates cancer cell survival and adaptation. Alterations in global gene expression are strongly impacted by post‐transcriptional gene regulation. The RNA binding protein (RBP) HuR (ELAVL1) is an established regulator of post‐transcriptional gene regulation and is overexpressed in most human cancers. In many cancerous settings, HuR is not only overexpressed, but it is “overactive” as denoted by increased subcellular localization within the cytoplasm. This dysregulation of HuR expression and cytoplasmic localization allows HuR to stabilize and increase the translation of various prosurvival messenger RNA (mRNAs) involved in the pathogenesis of numerous cancers and various diseases. Based on almost 20 years of work, HuR is now recognized as a therapeutic target. Herein, we will review the role HuR plays in the pathophysiology of different diseases and ongoing therapeutic strategies to target HuR. We will focus on three ongoing‐targeted strategies: (1) inhibiting HuR's translocation from the nucleus to the cytoplasm; (2) inhibiting the ability of HuR to bind target RNA; and (3) silencing HuR expression levels. In an oncologic setting, HuR has been demonstrated to be critical for a cancer cell's ability to survive a variety of cancer relevant stressors (including drugs and elements of the tumor microenvironment) and targeting this protein has been shown to sensitize cancer cells further to insult. We strongly believe that targeting HuR could be a powerful therapeutic target to treat different diseases, particularly cancer, in the near future. This article is categorized under: RNA in Disease and Development > RNA in Disease NRA Turnover and Surveillance > Regulation of RNA Stability Translation > Translation Regulation

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Section: Hur's Role In the Pathobiology Of Diseasementioning

confidence: 99%

Understanding and targeting the disease‐related RNA binding protein human antigen R (HuR)

et al. 2020

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“…Two alternative promoters and alternative splicing produce different transcripts that are generally less abundant than the canonical form. Interestingly, some of these transcripts have a truncated steroid‐binding domain and can either potentiate MR signalling (Zennaro et al, 2001) or act as dominant‐negative regulators (Lema et al, 2017) of the full‐length MR. Two additional isoforms due to alternative translation initiation sites have been proposed (Pascual‐Le Tallec et al, 2004), but their existence in vivo has not been demonstrated. In general, the biological relevance of MR isoforms is unclear, although it has been recently suggested that one of them acts as a general brake on MR signalling, which is released during hypotonic stress in the kidney (Lema et al, 2017).…”

Section: Gene Structure and Expression Regulationmentioning

confidence: 99%

Structural and molecular determinants of mineralocorticoid receptor signalling

Großmann

Almeida-Prieto

Nolze

et al. 2021

British J Pharmacology

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During the past decades, the mineralocorticoid receptor (MR) has evolved from a much-overlooked member of the steroid hormone receptor family to an important player, not only in volume and electrolyte homeostasis but also in pathological changes occurring in an increasing number of tissues, especially the renal and cardiovascular systems. Simultaneously, a wealth of information about the structure, interaction partners and chromatin requirements for genomic signalling of steroid hormone receptors became available. However, much of the information for the MR has been deduced from studies of other family members and there is still a lack of knowledge about MR-specific features in ligand binding, chromatin remodelling, co-factor interactions and general MR specificity-conferring mechanisms that can completely explain the differences in pathophysiological function between MR and its closest relative, the glucocorticoid receptor. This review aims to give an overview of the current knowledge of MR structure, signalling and co-factors modulating its activity.

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“…This transcription factor is encoded by the NR3C2 gene, which is located in humans at locus 4q31.1–4q31.2 [ 14 , 15 ] and encodes a 984 amino-acids protein (≈107 kDa) [ 16 ], organized into four distinct structural domains: the N-terminal domain (NTD), the DNA binding domain (DBD), the hinge region, and the ligand binding domain (LBD). MR functions were shown to be modulated by splice variants, lacking either exon 6 or both exon 5 and 6 [ 17 , 18 ]. Two major variants of human MR, named MRA and MRB, are generated by alternative initiation sites of translation from methionine 1 and 15, respectively.…”

Section: Mineralocorticoid Signaling Pathwaymentioning

confidence: 99%

Sexual Dimorphism of Corticosteroid Signaling during Kidney Development

Laulhé

Dumeige

et al. 2021

IJMS

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Sexual dimorphism involves differences between biological sexes that go beyond sexual characteristics. In mammals, differences between sexes have been demonstrated regarding various biological processes, including blood pressure and predisposition to develop hypertension early in adulthood, which may rely on early events during development and in the neonatal period. Recent studies suggest that corticosteroid signaling pathways (comprising glucocorticoid and mineralocorticoid signaling pathways) have distinct tissue-specific expression and regulation during this specific temporal window in a sex-dependent manner, most notably in the kidney. This review outlines the evidence for a gender differential expression and activation of renal corticosteroid signaling pathways in the mammalian fetus and neonate, from mouse to human, that may favor mineralocorticoid signaling in females and glucocorticoid signaling in males. Determining the effects of such differences may shed light on short term and long term pathophysiological consequences, markedly for males.

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HuR-Dependent Editing of a New Mineralocorticoid Receptor Splice Variant Reveals an Osmoregulatory Loop for Sodium Homeostasis

Cited by 8 publications

References 47 publications

Understanding and targeting the disease‐related RNA binding protein human antigen R (HuR)

Understanding and targeting the disease‐related RNA binding protein human antigen R (HuR)

Structural and molecular determinants of mineralocorticoid receptor signalling

Sexual Dimorphism of Corticosteroid Signaling during Kidney Development

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