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      The P-body component USP52/PAN2 is a novel regulator of HIF1A mRNA stability

      research-article
      Author(s): * , * , * , * , * , † , * , † , 1
      Publication date (Electronic):
      Journal: Biochemical Journal
      Publisher: Portland Press Ltd.
      Keywords: AU-rich element (ARE)-mediated degradation (AMD), hypoxia-inducible factor 1α (HIF1A), poly(A) nuclease 2 (PAN2), processing body (P-body), pseudo-deubiquitinating enzyme (pseudo-DUB), ubiquitin-specific protease 52 (USP52), aHIF, antisense hypoxia-inducible factor, ARE, AU-rich element, AMD, ARE-mediated degradation, CA9, carbonic anhydrase IX, CHX, cycloheximide, CTNNB1, β-catenin, CUL2, cullin 2, DCP1A, decapping enzyme 1A, DUB, deubiquitinating enzyme, ERG, Ets-related gene, FBS, fetal bovine serum, FISH, fluorescent in situ hybridization, GFP, green fluorescent protein, GLUT1, glucose transporter 1, HEK, human embryonic kidney, HIF1A, hypoxia-inducible factor 1α, HIF1B, hypoxia-inducible factor 1β, HRE, hypoxia-response element, LC, liquid chromatography, LDHA, lactate dehydrogenase A, miRNA, microRNA, MS/MS, tandem MS, NEDD8, neural-precursor-cell-expressed developmentally down-regulated 8, NP-40, Nonidet P40, NT, Non-Targeting, PABPC1, poly(A)-binding protein C1, PAN2, poly(A) nuclease 2, P-body, processing body, PHD, prolyl hydroxylase, RT, reverse transcription, siRNA, short interfering RNA, TCE, transcription elongation factor, TRIM21, tripartite motif-containing 21, TTP, tristetrapolin, USP52, ubiquitin-specific protease 52, UTR, untranslated region, VEGF, vascular endothelial growth factor, VHL, von Hippel–Lindau, YFP, yellow fluorescent protein

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          Abstract

          HIF1A (hypoxia-inducible factor 1α) is the master regulator of the cellular response to hypoxia and is implicated in cancer progression. Whereas the regulation of HIF1A protein in response to oxygen is well characterized, less is known about the fate of HIF1A mRNA. In the present study, we have identified the pseudo-DUB (deubiquitinating enzyme)/deadenylase USP52 (ubiquitin-specific protease 52)/PAN2 [poly(A) nuclease 2] as an important regulator of the HIF1A-mediated hypoxic response. Depletion of USP52 reduced HIF1A mRNA and protein levels and resulted in reduced expression of HIF1A-regulated hypoxic targets due to a 3′-UTR (untranslated region)-dependent poly(A)-tail-length-independent destabilization in HIF1A mRNA. MS analysis revealed an association of USP52 with several P-body (processing body) components and we confirmed further that USP52 protein and HIF1A mRNA co-localized with cytoplasmic P-bodies. Importantly, P-body dispersal by knockdown of GW182 or LSM1 resulted in a reduction of HIF1A mRNA levels. These data uncover a novel role for P-bodies in regulating HIF1A mRNA stability, and demonstrate that USP52 is a key component of P-bodies required to prevent HIF1A mRNA degradation.

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          Defining the human deubiquitinating enzyme interaction landscape.

          Mathew Sowa, Eric J Bennett, Steven Gygi … (2009)
          Deubiquitinating enzymes (Dubs) function to remove covalently attached ubiquitin from proteins, thereby controlling substrate activity and/or abundance. For most Dubs, their functions, targets, and regulation are poorly understood. To systematically investigate Dub function, we initiated a global proteomic analysis of Dubs and their associated protein complexes. This was accomplished through the development of a software platform called CompPASS, which uses unbiased metrics to assign confidence measurements to interactions from parallel nonreciprocal proteomic data sets. We identified 774 candidate interacting proteins associated with 75 Dubs. Using Gene Ontology, interactome topology classification, subcellular localization, and functional studies, we link Dubs to diverse processes, including protein turnover, transcription, RNA processing, DNA damage, and endoplasmic reticulum-associated degradation. This work provides the first glimpse into the Dub interaction landscape, places previously unstudied Dubs within putative biological pathways, and identifies previously unknown interactions and protein complexes involved in this increasingly important arm of the ubiquitin-proteasome pathway.
          Article 0 comments Cited 532 times – based on 0 reviews     Review now
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            A microRNA signature of hypoxia.

            Ritu Kulshreshtha, Manuela Ferracin, Sylwia E. Wojcik … (2007)
            Recent research has identified critical roles for microRNAs in a large number of cellular processes, including tumorigenic transformation. While significant progress has been made towards understanding the mechanisms of gene regulation by microRNAs, much less is known about factors affecting the expression of these noncoding transcripts. Here, we demonstrate for the first time a functional link between hypoxia, a well-documented tumor microenvironment factor, and microRNA expression. Microarray-based expression profiles revealed that a specific spectrum of microRNAs (including miR-23, -24, -26, -27, -103, -107, -181, -210, and -213) is induced in response to low oxygen, at least some via a hypoxia-inducible-factor-dependent mechanism. Select members of this group (miR-26, -107, and -210) decrease proapoptotic signaling in a hypoxic environment, suggesting an impact of these transcripts on tumor formation. Interestingly, the vast majority of hypoxia-induced microRNAs are also overexpressed in a variety of human tumors.
            Article 0 comments Cited 336 times – based on 0 reviews     Review now
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              P bodies: at the crossroads of post-transcriptional pathways.

              Ana Eulalio, Isabelle Behm-Ansmant, Elisa Izaurralde (2007)
              Post-transcriptional processes have a central role in the regulation of eukaryotic gene expression. Although it has been known for a long time that these processes are functionally linked, often by the use of common protein factors, it has only recently become apparent that many of these processes are also physically connected. Indeed, proteins that are involved in mRNA degradation, translational repression, mRNA surveillance and RNA-mediated gene silencing, together with their mRNA targets, colocalize within discrete cytoplasmic domains known as P bodies. The available evidence indicates that P bodies are sites where mRNAs that are not being translated accumulate, the information carried by associated proteins and regulatory RNAs is integrated, and their fate - either translation, silencing or decay - is decided.
              Article 0 comments Cited 232 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Biochem J
                Journal ID (iso-abbrev): Biochem. J
                Journal ID (pmc): bic
                Journal ID (publisher-id): BJ
                Title: Biochemical Journal
                Publisher: Portland Press Ltd.
                ISSN (Print): 0264-6021
                ISSN (Electronic): 1470-8728
                Publication date (Electronic preprint): 11 February 2013
                Publication date (Electronic): 28 March 2013
                Publication date (Print): 15 April 2013
                Volume: 451
                Issue: Pt 2
                Pages: 185-194
                Affiliations
                *Scottish Institute for Cell Signalling, Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
                †Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
                Author notes
                1To whom correspondence should be addressed (email R.T.Hay@ 123456dundee.ac.uk ).
                Article
                Publisher ID: BJ20130026
                DOI: 10.1042/BJ20130026
                PMC ID: 3632086
                PubMed ID: 23398456
                SO-VID: 9d25059c-dbaf-435a-b588-224e02e1d03a
                Copyright © © 2013 The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Licence (CC-BY)(http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 4 January 2013
                Date revision received : 31 January 2013
                Date accepted : 11 February 2013
                Page count
                Figures: 7, References: 40, Pages: 10
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Biochemistry
                Keywords: au-rich element (are)-mediated degradation (amd),hypoxia-inducible factor 1α (hif1a),poly(a) nuclease 2 (pan2),processing body (p-body),pseudo-deubiquitinating enzyme (pseudo-dub),ubiquitin-specific protease 52 (usp52),ahif, antisense hypoxia-inducible factor,are, au-rich element,amd, are-mediated degradation,ca9, carbonic anhydrase ix,chx, cycloheximide,ctnnb1, β-catenin,cul2, cullin 2,dcp1a, decapping enzyme 1a,dub, deubiquitinating enzyme,erg, ets-related gene,fbs, fetal bovine serum,fish, fluorescent in situ hybridization,gfp, green fluorescent protein,glut1, glucose transporter 1,hek, human embryonic kidney,hif1a, hypoxia-inducible factor 1α,hif1b, hypoxia-inducible factor 1β,hre, hypoxia-response element,lc, liquid chromatography,ldha, lactate dehydrogenase a,mirna, microrna,ms/ms, tandem ms,nedd8, neural-precursor-cell-expressed developmentally down-regulated 8,np-40, nonidet p40,nt, non-targeting,pabpc1, poly(a)-binding protein c1,pan2, poly(a) nuclease 2,p-body, processing body,phd, prolyl hydroxylase,rt, reverse transcription,sirna, short interfering rna,tce, transcription elongation factor,trim21, tripartite motif-containing 21,ttp, tristetrapolin,usp52, ubiquitin-specific protease 52,utr, untranslated region,vegf, vascular endothelial growth factor,vhl, von hippel–lindau,yfp, yellow fluorescent protein
                Data availability:
                ScienceOpen disciplines: Biochemistry
                Keywords: au-rich element (are)-mediated degradation (amd), hypoxia-inducible factor 1α (hif1a), poly(a) nuclease 2 (pan2), processing body (p-body), pseudo-deubiquitinating enzyme (pseudo-dub), ubiquitin-specific protease 52 (usp52), ahif, antisense hypoxia-inducible factor, are, au-rich element, amd, are-mediated degradation, ca9, carbonic anhydrase ix, chx, cycloheximide, ctnnb1, β-catenin, cul2, cullin 2, dcp1a, decapping enzyme 1a, dub, deubiquitinating enzyme, erg, ets-related gene, fbs, fetal bovine serum, fish, fluorescent in situ hybridization, gfp, green fluorescent protein, glut1, glucose transporter 1, hek, human embryonic kidney, hif1a, hypoxia-inducible factor 1α, hif1b, hypoxia-inducible factor 1β, hre, hypoxia-response element, lc, liquid chromatography, ldha, lactate dehydrogenase a, mirna, microrna, ms/ms, tandem ms, nedd8, neural-precursor-cell-expressed developmentally down-regulated 8, np-40, nonidet p40, nt, non-targeting, pabpc1, poly(a)-binding protein c1, pan2, poly(a) nuclease 2, p-body, processing body, phd, prolyl hydroxylase, rt, reverse transcription, sirna, short interfering rna, tce, transcription elongation factor, trim21, tripartite motif-containing 21, ttp, tristetrapolin, usp52, ubiquitin-specific protease 52, utr, untranslated region, vegf, vascular endothelial growth factor, vhl, von hippel–lindau, yfp, yellow fluorescent protein

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