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Far Upstream Element Binding Protein 1: a Commander of Transcription, Translation and Beyond

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Far Upstream Element Binding Protein 1: a Commander of Transcription, Translation and Beyond Oncogene (2013) 32, 2907–2916 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc REVIEW Far upstream element binding protein 1: a commander of transcription, translation and beyond J Zhang and QM Chen The far upstream binding protein 1 (FBP1) was first identified as a DNA-binding protein that regulates c-Myc gene transcription through binding to the far upstream element (FUSE) in the promoter region 1.5 kb upstream of the transcription start site. FBP1 collaborates with TFIIH and additional transcription factors for optimal transcription of the c-Myc gene. In recent years, mounting evidence suggests that FBP1 acts as an RNA-binding protein and regulates mRNA translation or stability of genes, such as GAP43, p27 Kip and nucleophosmin. During retroviral infection, FBP1 binds to and mediates replication of RNA from Hepatitis C and Enterovirus 71. As a nuclear protein, FBP1 may translocate to the cytoplasm in apoptotic cells. The interaction of FBP1 with p38/ JTV-1 results in FBP1 ubiquitination and degradation by the proteasomes. Transcriptional and post-transcriptional regulations by FBP1 contribute to cell proliferation, migration or cell death. FBP1 association with carcinogenesis has been reported in c-Myc dependent or independent manner. This review summarizes biochemical features of FBP1, its mechanism of action, FBP family members and the involvement of FBP1 in carcinogenesis. Oncogene (2013) 32, 2907–2916; doi:10.1038/onc.2012.350; published online 27 August 2012 Keywords: FBP1; FUSE; cancer INTRODUCTION IDENTIFICATION OF FBP1 The far upstream element binding protein 1 (FBP1) was first FBP1 was first cloned from a cDNA library generated from the discovered as a transcriptional regulator of the proto-oncogene undifferentiated human monoblastic line U937.6 Such an c-Myc. As a transcription factor, c-Myc controls the expression of approach was undertaken in an effort to understand how c-Myc about 10% of cellular genes, including those essential for cell transcription was downregulated in U937 and the human proliferation, differentiation and apoptosis.1–4 A large volume of promonomyelocytic leukemia HL60 cells upon induction of studies have led to the thorough characterization of signaling differentiation.22,23 Since its discovery, FBP1 has been found to pathways and transcription factors regulating the expression of be expressed in a variety of human cancer cell lines, including the c-Myc gene. Among the list of the regulators of c-Myc breast (MCF7 and MDA), colon (Colo 320DM, DLD1, HT29, LS180, transcription is FBP1, a single stranded DNA-binding protein SW48, SW480, SW620C and WiDr), prostate (PC3), cervix (HeLa), initially identified as the binding partner for the far upstream Burkitt’s lymphoma (Raji) and T-cell leukemia (Jurkat).24,25 element (FUSE), located B1.5 k base pairs (bp) upstream of the FBP1 binding to FUSE is required for maximal transcription of transcription start site in the c-Myc promoter. It was found that c-Myc gene. In a chloramphenicol acetyltransferase reporter assay the FUSE sequence specifically binds to one protein in with a 3.2-kb c-Myc promoter sequence fused to the chloram- undifferentiated but not differentiated cells,5 leading to the phenicol acetyltransferase coding sequence, elimination of FUSE discovery of FBP1 protein in 1994.6 In addition to FBP1 binding, resulted in an 80% reduction in c-Myc transcription.5 Several lines FUSE was later identified as a target of FBP-interacting repressor of evidence have indicated that FBP1 interaction with FUSE is (FIR). The interplay between FBP1, FIR and FUSE influences the critical for optimal c-Myc transcription. Avigan et al.5 reported that timing and maximal level of c-Myc gene expression.7 a DNA probe containing the FUSE sequence was recognized by a A number of recent reports have indicated that FBP1 is also an protein in the lysate of undifferentiated, but not differentiated, RNA-binding protein. RNA binding accounts for a role of FBP1 in HL60 cells in an Electrophoretic Mobility Shift Assay (EMSA). translation or stabilization of several cellular and viral mRNA Following identification of the protein as FBP1, subsequent studies species.8–11 These activities, together with c-Myc transcriptional have documented the presence of FBP1 mRNA and protein in control, place FBP1 at an eminent position in carcinogenesis.12–15 undifferentiated HL60 cells, which decline significantly after Aberrant expression of FBP1, mutations in the FBP1 gene or induction of differentiation with dimethyl sulfoxide and 12-O- alternative splicing of its repressor FIR have been found in a variety tetradecanohlphorbol 13-acetate.6,24 This expression pattern is of malignant tissues.16–19 In addition to its role in carcinogenesis, consistent with the reduction of FUSE-binding activity and FBP1 is important for the development of certain organs, such as the c-Myc transcription, and consequently commitment to cell lung20 and neural system.9,21 FBP1 binding to viral RNA contributes to differentiation.6,24 Overexpression of the FBP1 gene led to a several viral diseases, including hepatitis C, and hand-foot-mouth fivefold increase in FUSE-mediated transcription as measured with disease. Despite the prominent role of FBP1 in transcription, mRNA a c-Myc promoter chimeric chloramphenicol acetyltransferase stability and translation, FBP1 remains a mystery to many. reporter. This increase was specific for the interaction of FBP1 with Department of Pharmacology, University of Arizona, Tucson, AZ, USA. Correspondence: Dr QM Chen, Department of Pharmacology, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724, USA. E-mail: [email protected] Received 27 December 2011; revised 26 June 2012; accepted 26 June 2012; published online 27 August 2012 FBP1: a commander of transcription, translation and beyond J Zhang and QM Chen 2908 the FUSE sequence, as FBP1 failed to stimulate the reporter protein containing 10 subunits, exhibits p89/XPB/ERCC3 and downstream of a c-Myc promoter sequence containing mutated p80/XPD/ERCC2 DNA helicase activities.32 FBP1 binding stimulates FUSE.6 p89/XBP/ERCC3 30-50 helicase activity of TFIIH, which mediates The physical interaction of FBP1 with FUSE has been demon- c-Myc promoter melting.31 Interestingly, FBP1 itself has an ATP- strated with copious lines of evidence in vitro and in vivo as dependent 30-50 helicase activity and is known as DNA Helicase V. summarized in Table 1. Electrophoretic mobility shift assays Such helicase activity allows FBP1 to unwind DNA–DNA and RNA– (EMSAs) showed that recombinant FBP1 or FBP1 protein purified RNA duplexes in vitro.33,34 This helicase activity is likely mediated from HL60 cells bound to the oligonucleotides containing the by the Argine-Glycine-Glycine (RGG) motifs at the C-terminus, as FUSE sequence.6 Detailed analyses revealed that FBP1 bound to this motif is conserved among several proteins exhibiting helicase non-coding strands of FUSE in vitro and in vivo, as FBP1 protected activity, for example, nucleolin and Ras-GAP SH3 domain-binding this strand, but not the coding strand, from potassium protein (G3BP/helicase VIII).35 The helicase activity of FBP1 may permanganate modification of unpaired thymine and sub- have a role in unwinding the DNA duplex around FUSE to sustain sequent cleavage by piperidine.6,26 The discovery of FBP1 set a c-Myc transcription.34 new milestone for understanding of transcriptional regulation of The FBP1 gene is conserved in eukaryotes, sharing over 90% the c-Myc gene. sequence homology among mammalian species. Screening of the FBP FAMILY MEMBERS The human FBP1 gene (NM_003902.3), also known as FUBP1 (far upstream binding protein 1), encodes a 644-amino acid protein with three well-defined domains: an amphipathic helix N-terminal domain, a tyrosine-rich C-terminal transactivation domain and a DNA-binding central domain (Figure 1).6,27 The N-terminal domain represses the activity of the C-terminal domain,27 suggesting that FBP1 protein folds into an enclosed conformation in an inactive state and undergoes a conformational change upon activation. The DNA-binding central domain contains four K-homology (KH) motifs, the conserved a-helices with a hydrophobic core first identified from heterogeneous nuclear ribonucleoprotein K.28 Each of the tandem KH domains is followed by an adjacent amphipathic helix (Figure 1). KH3 together with the KH4 domain is sufficient for FUSE binding in vitro, as the GXXG motif in KH3 or KH4 domain bound to a single stranded 50-dTTTT or 50-dATTC Figure 1. Schematic structure of human FBP1 protein. The N-termi- sequence of FUSE in vitro, respectively.29 When the central nus is composed of amino acid residues 1–106. The central domain domain, that is, FBPcd, was expressed ectopically, it acted as a spans amino acid residues 107–447 and is responsible for DNA 30 binding. The C-terminus contains amino acid residues 448–644, dominant negative competitor for endogenous FBP1. including three YM motifs. The well-defined NLS sequences and The transactivation domain at the C-terminus (448–644 localizations at the N-terminus and the Central domain are aminoacid residues) contains three tyrosine-rich motifs (YM). illustrated. Two isoleucines I378 and I379, important for FBP1 Such a structural feature is important for physical interaction of localization, are underlined. The caspase cleavage site, DQPD, is FBP1 with TFIIH, a basal transcription factor.31 TFIIH, a multimeric marked with asterisks. The domains are not drawn proportional. Table
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