An RNA-Binding Protein Family That Provides a Link Between Stem Cell Maintenance in Normal Development and Cancer
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Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer Nils Degrauwe,1 Mario-Luca Suvà,2 Michalina Janiszewska,3 Nicolo Riggi,4 and Ivan Stamenkovic4 1Department of Medicine, Centre Hospitalier Universitaire Vaudois/University of Lausanne, Lausanne CH-1011, Switzerland; 2Molecular Pathology Unit, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA; 3Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA; 4Experimental Pathology Service, Centre Hospitalier Universitaire Vaudois/University of Lausanne, Lausanne CH-1011, Switzerland IMPs, also known as insulin-like growth factor 2 (IGF2) may have as many as hundreds to thousands of mRNA tar- messenger RNA (mRNA)-binding proteins (IGF2BPs), gets (Hafner et al. 2010; Anko and Neugebauer 2012; are highly conserved oncofetal RNA-binding proteins Ascano et al. 2012) and serve as structural components (RBPs) that regulate RNA processing at several levels, in- of messenger ribonucleoprotein particles (mRNPs), in cluding localization, translation, and stability. Three which mRNAs are transported from the nucleus to the mammalian IMP paralogs (IMP1–3) have been identified cytoplasm and whose composition helps determine that are expressed in most organs during embryogenesis, transcript fate (Muller-McNicoll and Neugebauer 2013). where they are believed to play an important role in cell As many RBPs lack enzymatic activity, they can exert migration, metabolism, and stem cell renewal. Whereas some of their regulatory functions by recruiting additional some IMP2 expression is retained in several adult mouse proteins, which may include decay enzymes and transla- organs, IMP1 and IMP3 are either absent or expressed at tional repressors (Moore and Proudfoot 2009; Schoenberg very low levels in most tissues after birth. However, all and Maquat 2012). RBPs thereby not only add to the three paralogs can be re-expressed upon malignant trans- structural and functional diversity of mRNPs but, more formation and are found in a broad range of cancer types importantly, orchestrate the composition of RNA pro- where their expression often correlates with poor progno- cessing effector complexes to which they confer sequence sis. IMPs appear to resume their physiological functions specificity. in malignant cells, which not only contribute to tumor RBPs share post-transcriptional regulation of mRNA progression but participate in the establishment and stability with microRNAs (miRNAs), 21- to 22-nucleotide maintenance of tumor cell hierarchies. This review sum- (nt) noncoding RNAs (ncRNAs) that mediate post- marizes our current understanding of the functions of transcriptional silencing by target mRNA degradation or IMPs during normal development and focuses on a series translational repression (Bartel 2009) and are implicated of recent observations that have provided new insight into in the regulation of virtually all biological processes in how their physiological functions enable IMPs to play a multicellular organisms (He and Hannon 2004; Ivey and potentially key role in cancer stem cell maintenance Srivastava 2010). miRNA biogenesis is a multistep pro- and tumor growth. cess that is not discussed here, and we refer readers to sev- eral excellent reviews (Ha and Kim 2014; Lin and Gregory 2015). RNA-binding proteins (RBPs) regulate gene expression by MiRNAs and RBPs can exert synergistic or opposing intervening at all stages of messenger RNA (mRNA) me- effects on target mRNAs (for review, see van Kouwen- tabolism, including transcription, 5′ end capping, precur- hove et al. 2011; Ciafre and Galardi 2013; Ho and Marsden sor mRNA splicing, 3′ end processing, nuclear export, 2014). RBPs can cooperate with miRNAs to effect mRNA transport, translation, and stability (for review, see Mul- destabilization by recruiting miRNA-containing RNA- ler-McNicoll and Neugebauer 2013). Individual RBPs © 2016 Degrauwe et al. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue [Keywords: cancer; IGF2BP; IMP; RNA binding proteins; let-7; stem cells] publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). Corresponding author: [email protected] After six months, it is available under a Creative Commons License (At- Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.287540. tribution-NonCommercial 4.0 International), as described at http:// 116. creativecommons.org/licenses/by-nc/4.0/. GENES & DEVELOPMENT 30:2459–2474 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/16; www.genesdev.org 2459 Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Degrauwe et al. induced silencing complexes (RISCs), the core of which observed to control the subcellular localization of β-actin consists of Argonaute proteins (AGO1–4) (for review, see mRNA in primary mammalian fibroblasts (Farina et al. Ha and Kim 2014), to target mRNAs (Jing et al. 2005; 2003) and neurons (Tiruchinapalli et al. 2003) by binding Kim et al. 2009; Glorian et al. 2011) or altering the second- to the cis-acting zipcode in the 3′ UTR. Human IMP2, ary structure of target mRNAs to render miRNA-binding which has diverged phylogenetically from IMP1 and sites more accessible (Kedde et al. 2010). Conversely, IMP3 and has no known orthologs, was discovered as a re- RBPs can compete with miRNAs for binding to or in sult of its binding to IGF2 transcripts (Nielsen et al. 1999). the vicinity of miRNA recognition binding sites (also It was also referred to as p62, reflecting the molecular referred to as miRNA recognition elements [MREs]) on mass of one of its splice variants, and was proposed to be target mRNAs, including their own, and protect tran- an autoantigen in hepatocellular carcinoma (HCC) (Zhang scripts from miRNA-dependent degradation (Kedde et al. et al. 1999a). Single-nucleotide polymorphisms (SNPs) 2007; Kundu et al. 2012; Young et al. 2012; Xue et al. have been identified in the second intron of the IMP2 2013). In some situations, the same RBP can exert a gene that correlate with elevated risk of type 2 diabetes stabilizing or destabilizing effect on different target (Christiansen et al. 2009). IMP3, a Vg1-RBP/Vera ortholog mRNAs, depending on its interplay with miRNAs that initially called KOC, was identified on the basis of its associate with the same transcripts (Srikantan et al. abundance in pancreatic cancer (Mueller-Pillasch et al. 2012). Determination of mRNA fate by this complex 1997). It was subsequently shown to be expressed by a relationship between RBPs and miRNAs affects a broad broad range of tumors, and its expression was often found panel of physiological and pathological events from to correlate with poor prognosis (for review, see Lederer embryogenesis and differentiation to transformation et al. 2014). and tumorigenesis. Among the ∼600 RBPs annotated in mammalian ge- nomes based on their content of known RBPs and 800 can- Physiological expression of IMP family members didate RBPs identified in cell lines using new high- throughput ultraviolet (UV) cross-linking technologies Physiological expression of IMPs occurs primarily during (Baltz et al. 2012; Castello et al. 2012), relatively few development. Mammalian IMPs display a biphasic expres- have been associated with cancer. RBPs with a recognized sion pattern, first appearing in the oocyte and zygote (Niel- role in tumor growth and progression include the TET sen et al. 2001; Yaniv and Yisraeli 2002) and subsequently family (Riggi et al. 2007), the STAR family (Elliott and displaying up-regulation on mouse embryonic day 10.5 Rajan 2010), β-catenin (Lee et al. 2007; Kim et al. 2012), (E10.5) to E12.5 (Nielsen et al. 1999; Runge et al. 2000). LIN28A and LIN28B (Viswanathan et al. 2009; Nguyen At mid-gestation, IMPs are expressed in most developing et al. 2014), and several RBPs involved in RNA splicing tissues, their expression being highest in neuronal and (David and Manley 2010). Recent work from several labo- epithelial cells. Imp1 and Imp3 transcripts are expressed ratories has shown that the IMP family of oncofetal RBPs in the forebrain and hindbrain, the snout, the branchial can promote carcinogenesis in part by regulating miRNA arches, the gut, the tail, the vertebrae, and the skin (Muel- activity. ler-Pillasch et al. 1999; Mori et al. 2001; Hansen et al. Three mammalian IMP paralogs—IMP1–3, also known 2004). A similar expression pattern is observed in Xeno- as insulin-like growth factor 2 (IGF2) mRNA-binding pro- pus, zebrafish, and Drosophila (Mueller-Pillasch et al. teins 1, 2, and 3 (IGF2BP1–3)—have been identified thus 1999; Zhang et al. 1999b; Nielsen et al. 2000; Adolph far. They belong to the family of zipcode-binding proteins et al. 2009). Detailed assessment of expression in mouse initially proposed to bear the acronym VICKZ based on brains revealed that, at E10.5, Imp1 is expressed through- the first letter of its founding members (Yaniv and Yisraeli out the ventricular zone (VZ) of the entire developing brain 2002), which include Vegetal-1 mRNA-binding protein with the exception of the floor and roof plates. Between (Vg1RBP/Vera) in Xenopus laevis; IMP1–3 in mammals; E12.5 and E16.5, Imp1 expression gradually becomes coding region