Posttranslational control of <scp>HuR</scp> function

Grammatikakis, Ioannis; Abdelmohsen, Kotb; Gorospe, Myriam

doi:10.1002/wrna.1372

Cited by 200 publications

(233 citation statements)

References 98 publications

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“…As shown in Figure A, circ‐CCND1 was predominately localized in the cytoplasm, which is consistent with its post‐transcriptional regulation of CCND1. By the online CircInteractome tool, we found that circ‐CCND1 can interact with some RNA‐binding proteins, in which human antigen R (HuR) attracted our attention mainly due to its function of RNA stabilization . RNA pull‐down results showed that a large amount of HuR protein was enriched by circ‐CCND1 probe, but not control probe, and it was diminished when circ‐CCND1 was depleted (Figure B).…”

Section: Resultsmentioning

confidence: 99%

circRNA circ‐CCND1 promotes the proliferation of laryngeal squamous cell carcinoma through elevating CCND1 expression via interacting with HuR and miR‐646

Zang

Wan

et al. 2020

J Cellular Molecular Medi

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Cyclin D1 (CCND1) is a well‐known proliferation promoter that accelerates G1/S transition in cancer. However, the underlying mechanism by which CCND1 is regulated is still largely unknown. In this study, we identified a novel circular RNA (circRNA) derived from CCND1 (circ‐CCND1, hsa_circ_0023303) as a key regulator for CCND1. circ‐CCND1 was found to be markedly up‐regulated in laryngeal squamous cell carcinoma (LSCC) and closely associated with aggressive clinical features and adverse prognosis. Depletion of circ‐CCND1 significantly inhibited LSCC cell proliferation in vitro and retarded tumour growth in vivo. Regarding the mechanism, circ‐CCND1 physically bound to human antigen R (HuR) protein to enhance CCND1 mRNA stability; on the other hand, circ‐CCND1 could act as an effective sponge for miR‐646 to alleviate the repression of miR‐646 on CCND1 mRNA. As a result, circ‐CCND1 post‐transcriptionally elevated CCND1 expression via coordinated avoidance of CCND1 mRNA decay, thereby promoting LSCC tumorigenesis. Taken together, our findings uncover the essential proliferation‐promoting role of circ‐CCND1 through regulation of the stability of CCND1 mRNA in LSCC. Targeting circ‐CCND1 may be a promising treatment for LSCC patients.

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Section: Resultsmentioning

confidence: 99%

circRNA circ‐CCND1 promotes the proliferation of laryngeal squamous cell carcinoma through elevating CCND1 expression via interacting with HuR and miR‐646

Zang

Wan

et al. 2020

J Cellular Molecular Medi

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“…When in cytosol, HuR attaches to AU-rich sections in 3′-untranslated regions of mRNAs involved in cell proliferation, apoptosis and differentiation. HuR binding protects transcripts from degradation and regulates translation (Meisner & Filipowicz, 2011; Grammatikakis et al, 2016). HuR binding with apo-CRABP2 enhances its affinity for select mRNAs >3 orders of magnitude, i.e.…”

Section: Crabps Perform Multiple Tasks Fundamental To Atra Metabolmentioning

confidence: 99%

Cellular retinoid binding-proteins, CRBP, CRABP, FABP5: Effects on retinoid metabolism, function and related diseases

Napoli

2017

Pharmacology & Therapeutics

195

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Cellular binding-proteins (BP), including CRBP1, CRBP2, CRABP1, CRABP2, and FABP5, shepherd the poorly aqueous soluble retinoids during uptake, metabolism and function. Holo-BP promote efficient use of retinol, a scarce but essential nutrient throughout evolution, by sheltering it and its major metabolite all-trans-retinoic acid from adventitious interactions with the cellular milieu, and by imposing specificity of delivery to enzymes, nuclear receptors and other partners. Apo-BP reflect cellular retinoid status and modify activities of retinoid metabolon enzymes, or exert non-canonical actions. High ligand binding affinities and the nature of ligand sequestration necessitate external factors to prompt retinoid release from holo-BP. One or more of cross-linking, kinetics, and colocalization have identified these factors as RDH, RALDH, CYP26, LRAT, RAR and PPARβ/δ. Michaelis-Menten and other kinetic approaches verify that BP channel retinoids to select enzymes and receptors by protein-protein interactions. Function of the BP and enzymes that constitute the retinoid metabolon depends in part on retinoid exchanges unique to specific pairings. The complexity of these exchanges configure retinol metabolism to meet the diverse functions of all-trans-retinoic acid and its ability to foster contrary outcomes in different cell types, such as inducing apoptosis, differentiation or proliferation. Altered BP expression affects retinoid function, for example, by impairing pancreas development resulting in abnormal glucose and energy metabolism, promoting predisposition to breast cancer, and fostering more severe outcomes in prostate cancer, ovarian adenocarcinoma, and glioblastoma. Yet, the extent of BP interactions with retinoid metabolon enzymes and their impact on retinoid physiology remains incompletely understood.

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“…4 In addition, it can modulate the splicing of several target pre-mRNAs and enhance the nuclear export of some mRNAs (reviewed in Ref. 5). HuR can also interact with several noncoding (nc)RNAs.…”

Section: Introductionmentioning

confidence: 99%

“…HuR binding to target mRNAs is modulated by HuR phosphorylation by kinases like CHEK2, PKC, and JAK3, and by methylation through CARM1. 5 As these post-translational modifications affect the subcellular localization of HuR and its association with target RNAs, it will be important to investigate if they (right), the levels of PABPN1, HuR, and the loading control HSP90 were assessed by Western blot analysis. Following quantification of the bands on Western blots, the relative signal intensities were represented as the means § SEM from three independent experiments.…”

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confidence: 99%

Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1

et al. 2017

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HuR influences gene expression programs and hence cellular phenotypes by binding to hundreds of coding and noncoding linear RNAs. However, whether HuR binds to circular RNAs (circRNAs) and impacts on their function is unknown. Here, we have identified en masse circRNAs binding HuR in human cervical carcinoma HeLa cells. One of the most prominent HuR target circRNAs was hsa_circ_0031288, renamed CircPABPN1 as it arises from the PABPN1 pre-mRNA. Further analysis revealed that HuR did not influence CircPABPN1 abundance; interestingly, however, high levels of CircPABPN1 suppressed HuR binding to PABPN1 mRNA. Evaluation of PABPN1 mRNA polysomes indicated that PABPN1 translation was modulated positively by HuR and hence negatively by CircPABPN1. We propose that the extensive binding of CircPABPN1 to HuR prevents HuR binding to PABPN1 mRNA and lowers PABPN1 translation, providing the first example of competition between a circRNA and its cognate mRNA for an RBP that affects translation.

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Posttranslational control of HuR function

Cited by 200 publications

References 98 publications

circRNA circ‐CCND1 promotes the proliferation of laryngeal squamous cell carcinoma through elevating CCND1 expression via interacting with HuR and miR‐646

circRNA circ‐CCND1 promotes the proliferation of laryngeal squamous cell carcinoma through elevating CCND1 expression via interacting with HuR and miR‐646

Cellular retinoid binding-proteins, CRBP, CRABP, FABP5: Effects on retinoid metabolism, function and related diseases

Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1

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