3’UTR Shortening Potentiates MicroRNA-Based Repression of Pro-differentiation Genes in Proliferating Human Cells

Hoffman, Yonit; Bublik, Debora Rosa; Ugalde, Alejandro P.; Elkon, Ran; Biniashvili, Tammy; Agami, Reuven; Oren, Moshe; Pilpel, Yitzhak

doi:10.1371/journal.pgen.1005879

Cited by 82 publications

(72 citation statements)

References 29 publications

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“…Relative luciferase activity was significantly reduced in premiR-210-treated cells, suggesting that miR-210 targets APC through its 3′-UTR ( Figure 1F; Online Figure IIC and IID). 34 In the search for potential miR-210 binding sites at the APC 3′-UTR, we used the RNA22 program as described previously. 18 We identified 3 putative miR-210 binding sites (BS-1, …”

Section: Eken Et Al Mir-210 Enhances Atherosclerotic Plaque Stabilitymentioning

confidence: 99%

MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions

Eken

Jin

Chernogubova

et al. 2017

Circulation Research

110

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Stroke is the second most common cause of death 2 and major cause of disability worldwide, 2 with survivors often depending on lifelong care. Carotid stenosis is the second most common predecessor of ischemic stroke, 3 and carotid endarterectomy (CEA; and to a lesser extent carotid artery stenting) are accepted as secondary, but also primary preventive therapy. 2,4,5 With new imaging techniques, vulnerable plaques at risk of rupture can be identified with increasing accuracy, 6 but in the majority of cases, the perioperative surgical risk of ≈3% still outweighs the risk of plaque rupture in asymptomatic carotid stenosis carriers.7 As a result, CEA and carotid artery stenting are currently unfavorable for most of these individuals.8 Detection and stabilization of a vulnerable plaque by influencing the local disease process biologically would provide a sophisticated solution for asymptomatic plaque carriers at risk of stroke. Molecular Medicine© 2016 American Heart Association, Inc. Conclusions: An unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic vascular events.

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Section: Eken Et Al Mir-210 Enhances Atherosclerotic Plaque Stabilitymentioning

confidence: 99%

MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions

Eken

Jin

Chernogubova

et al. 2017

Circulation Research

110

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“…Importantly, both microRNAs (miRNAs) and RNA binding proteins (RBPs) targeting 3 ′ UTRs are able to regulate translational efficiency, degradation, and subcellular localization of mRNA or protein (Di Giammartino et al 2011;Berkovits and Mayr 2015;Tian and Manley 2017). It is well known that APA plays important roles in a wide range of biological processes such as cell differentiation (Ji et al 2009;Mangone et al 2010;Hilgers et al 2011;Ulitsky et al 2012;Fu et al 2016;Hu et al 2017), cell proliferation Elkon et al 2012;Hoffman et al 2016), cell/tissue identity Derti et al 2012;Smibert et al 2012;Ni et al 2013), and carcinogenesis (Mayr and Bartel 2009;Fu et al 2011;Lin et al 2012;Xia et al 2014). However, whether APA is involved in senescenceassociated gene expression and contributes to cellular senescence remains to be answered.…”

mentioning

confidence: 99%

3′ UTR lengthening as a novel mechanism in regulating cellular senescence

Chen¹,

Lyu

Han³

et al. 2018

Genome Res.

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Cellular senescence has been viewed as a tumor suppression mechanism and also as a contributor to individual aging. Widespread shortening of 3 ′ untranslated regions (3 ′ UTRs) in messenger RNAs (mRNAs) by alternative polyadenylation (APA) has recently been discovered in cancer cells. However, the role of APA in the process of cellular senescence remains elusive. Here, we found that hundreds of genes in senescent cells tended to use distal poly(A) (pA) sites, leading to a global lengthening of 3 ′ UTRs and reduced gene expression. Genes that harbor longer 3 ′ UTRs in senescent cells were enriched in senescence-related pathways. Rras2, a member of the Ras superfamily that participates in multiple signal transduction pathways, preferred longer 3 ′ UTR usage and exhibited decreased expression in senescent cells. Depletion of Rras2 promoted senescence, while rescue of Rras2 reversed senescence-associated phenotypes. Mechanistically, splicing factor TRA2B bound to a core "AGAA" motif located in the alternative 3 ′ UTR of Rras2, thereby reducing the RRAS2 protein level and causing senescence. Both proximal and distal poly(A) signals showed strong sequence conservation, highlighting the vital role of APA regulation during evolution. Our results revealed APA as a novel mechanism in regulating cellular senescence.

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“…This finding may suggest 3′-UTR shortening to provide an additional repression mechanism for antiproliferative genes ( Hoffman et al 2016).…”

Section: Apamentioning

confidence: 85%

Alternative polyadenylation and RNA-binding proteins

Erson-Bensan

2016

Journal of Molecular Endocrinology

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Our understanding of the extent of microRNA-based gene regulation has expanded in an impressive pace over the past decade. Now, we are beginning to better appreciate the role of 3′-UTR (untranslated region) cis-elements which harbor not only microRNA but also RNA-binding protein (RBP) binding sites that have significant effect on the stability and translational rate of mRNAs. To add further complexity, alternative polyadenylation (APA) emerges as a widespread mechanism to regulate gene expression by producing shorter or longer mRNA isoforms that differ in the length of their 3′-UTRs or even coding sequences. Resulting shorter mRNA isoforms generally lack cis-elements where trans-acting factors bind, and hence are differentially regulated compared with the longer isoforms. This review focuses on the RBPs involved in APA regulation and their action mechanisms on APA-generated isoforms. A better understanding of the complex interactions between APA and RBPs is promising for mechanistic and clinical implications including biomarker discovery and new therapeutic approaches.

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3’UTR Shortening Potentiates MicroRNA-Based Repression of Pro-differentiation Genes in Proliferating Human Cells

Cited by 82 publications

References 29 publications

MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions

MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions

3′ UTR lengthening as a novel mechanism in regulating cellular senescence

Alternative polyadenylation and RNA-binding proteins

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