FUBP1 (far upstream element (FUSE) binding protein 1)

2013-05-01   Katharina Gerlach , Martin Zörnig 

Institute for Biomedical Research Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt, Germany

Identity

HGNC
LOCATION
1p31.1
LOCUSID
ALIAS
FBP,FUBP,hDH
FUSION GENES

DNA/RNA

Description

The human FUBP1 gene is located on the reverse strand of chromosome 1 (bases 78413591 to 78444777; according to NCBI Refseq Gene Database (gene ID: 8880, RefSeq ID: NM_003902.3), genome assembly GRCh37 from February 2009) of the human genome and is comprised of 31187 bp.
FUBP1 is composed of 20 protein-coding exons ranging between approx. 40 bp and 170 bp in length and 19 introns which vary greatly in size (approx. 100 bp - 8800 bp). It has a short (approx. 90 bp) 5 untranslated region (UTR) and a long 3 UTR (approx. 860 bp).
According to the Ensembl genome browser database 14 transcript variants of human FUBP1 have been reported (ENSG00000162613). One of them is composed of 21 exons (ENST00000436586).

Transcription

According to NCBI the human FUBP1 gene encodes a 2884 bp mRNA transcript, the coding sequence (CDS) located from base pairs 90 to 2024 (NM_003902.3). The CDS from the Ensembl genome browser database (ENST00000370768, transcript length 2378 bp) and NCBI (NM_003902.3) are identical. Transcripts NM_003902.3 and ENST00000370768 are also included in the human CCDS set (CCDS683) and encode a 644 aa long protein.

Pseudogene

None known.

Proteins

Atlas Image
Figure 1. FUBP1 is composed of an N-terminal domain, a central DNA-binding domain containing four KH (K homology) motifs and a C-terminal domain (with three tyrosine-rich motifs). A flexible linker domain connects the central and the C-terminal domain. The numbers above the diagram indicate the amino acid positions of the domains. Sites of the nuclear localization signals (NLS) are indicated. Adapted from Duncan et al., 1996.

Description

Human FUBP1 is composed of 644 amino acids, has a calculated molecular mass of 67,5 kDa and consists of three different protein domains. The N-terminal domain (amino acids 1 to 106) is able to repress transcriptional activation mediated by the C-terminal transactivation domain. The central domain (amino acids 107 to 447) contains four conserved KH motifs (K homology motif, first identified in the human heterogeneous nuclear ribonucleoprotein K protein (hnRNP K) (Siomi et al., 1993)) which facilitate the binding of FUBP1 to a single stranded DNA element (FUSE element, Braddock et al., 2002). A flexible glycine/proline-rich linker (amino acids 448 - 511) connects the central domain with the C-terminal transactivation domain (amino acids 448 - 644). This region contains three tyrosine-rich motifs which are required to activate transcription (Duncan et al., 1996; Duncan et al., 1994). Nuclear trafficking of FUBP1 is mediated by three nuclear localization signals (NLS): a classical NLS in the N-terminal domain and two non-canonical signals in the third KH motif and the third tyrosine-rich motifs (He et al., 2000b).

Expression

Widely expressed (Su et al., 2004).

Localisation

Nucleus (He et al., 2000b).

Function

FUBP1 is a transcriptional regulator and fulfills an important function in the precise control of c-myc transcription (mechanism described below). The c-Myc protein is a transcription factor which regulates the transcription of many different target genes that play a role in proliferation, cell cycle progression, differentiation, apoptosis and cell metabolism. Consequently, FUBP1 is also involved in the regulation of proliferation and differentiation, as confirmed by different experimental approaches. Knockdown of FUBP1 or expression of a dominant-negative FUBP1 (DNA-binding domain lacking effector activity) led to proliferation arrest in U2OS and Saos-2 osteosarcoma cells due to reduced c-myc expression (He et al., 2000a). Upon induction of differentiation in leukemia cells (HL-60 and U937), binding activity of FUBP1 to the c-myc promoter is lost. This indicates an important role of FUBP1 in maintaining c-myc transcription to prevent its downregulation and differentiation (Avigan et al., 1990).
As the KH motifs were first found to be involved in RNA-binding, it is not surprising that FUBP1 also interacts with specific RNAs. It was shown that FUBP1 interacts with the 3 UTR of GAP-43 mRNA (encoding a membrane phosphoprotein that is important for the development and plasticity of neuronal cells), hepatitis C virus RNA, nucleophosmin mRNA (a nucleolar oncoprotein involved in several cellular processes) and the 5 UTR of the p27 mRNA (a cyclin dependent kinase inhibitor), regulating their stabilities and translation (Irwin et al., 1997; Olanich et al., 2011; Zhang et al., 2008; Zheng and Miskimins, 2011). Although the regulatory mechanisms behind these interactions are still not fully characterized, these results implicate additional functions of FUBP1 in the regulation of neuronal differentiation, viral replication, cell growth and cell cycle progression.

Transcriptional regulation of the c-myc promoter by the FUBP family
Because of the unconventional binding properties of FUBP1 (single stranded DNA (ssDNA) instead of double stranded DNA (dsDNA) as for most other regular transcription factors), its mechanism in the regulation of c-myc transcription has been extensively studied. In the absence of serum, the c-myc locus is transcriptionally inactive. In this state, the FUSE element upstream of the promoter is in a double stranded conformation and masked by a nucleosome. Upon addition of serum, chromatin remodelling occurs, which results in the exposure of the FUSE element (Brooks and Hurley, 2009). Basal transcription of c-myc is initiated and leads to torsional stress and negative supercoiling of the DNA. Under sufficient supercoiling, the DNA of the AT-rich FUSE element melts and enables binding of FUBP3, which later is replaced by FUBP1 (Chung et al., 2006; Kouzine et al., 2008; Kouzine et al., 2004; Michelotti et al., 1996). Upon recruitment, FUBP1 interacts with the general transcription factor TFIIH and enhances its helicase activity, thereby facilitating promoter escape of the polymerase complex which enhances transcription of c-myc (Bazar et al., 1995; Liu et al., 2001). Therefore, c-myc transcription reaches a maximum approx. two hours after serum addition.
Shortly after reaching the maximal transcription rate, FBP interacting repressor (FIR) binds to the FUSE element and FUBP1, forming a stable tripartite FUSE-FUBP1-FIR complex. This complex reverts the activated transcription back to a basal level, due to FIR-mediated inhibition of the 3 to 5 helicase activity of TFIIH (Brooks and Hurley, 2009; Hsiao et al., 2010; Liu et al., 2000). Shorty after formation of the tripartite complex, FUBP1 is ejected while FIR remains bound to the FUSE element. This mechanism results in a sharp peak of c-myc expression upon serum addition (or other c-myc-inducing signals) and ensures the precise control of c-myc expression, which is important in normal cell homeostasis (Kelly and Siebenlist, 1986).

Homology

Two FUBP1 homologs, termed FUBP2/KHSRP and FUBP3, were also identified in the human genome. The three FUBP family members share the same protein architecture (three distinct domains). The central DNA-binding domain containing four KH motifs is the most conserved domain with 81,5% (FUBP2) and 80,9% (FUBP3) amino acids sequence homology to FUBP1 (Davis-Smyth et al., 1996). Although these proteins are highly conserved in their DNA-binding domains, divergences in their N- and C-termini lead to important functional differences. The C-terminal transactivation domain of FUBP3 is by far the strongest of the FBP family members. Furthermore, variations in its N-terminal domain seem to prevent an interaction with the FBP interacting repressor (FIR) (Chung et al., 2006). As described in the previous paragraph these characteristics are important for the transcriptional regulation of the c-myc gene. The transactivation domain of FUBP1 shows an intermediate strength whereas the one of FUBP2 displays the weakest activation capability. In contrast to FUBP3, FUBP1 and FUBP2 are able to interact with FIR (Chung et al., 2006). The weak transactivation domain already implicates that FUBP2 might not function as an important activator of transcription. In fact, FUBP2 (also named K homology splicing regulatory protein (KHSRP)) was shown to function as an mRNA binding protein, playing a role in mRNA splicing, trafficking, stabilization and degradation (Gherzi et al., 2004; Min et al., 1997).

Mutations

Somatic

Numerous reports about somatic mutations leading to the inactivation of FUBP1 in human oligodendrogliomas, oligoastrocytomas and astrocytomas (Bettegowda et al., 2011; Sahm et al., 2012; Jiao et al., 2012; Idbaih et al., 2012).

Implicated in

Entity name
Various cancers
Note
FUBP1 is a potential oncogene that is overexpressed in different cancer entities.
Its expression is strongly increased in NSCLC cells compared to non-tumorous lung tissues. Furthermore it was shown that FUBP1 coordinates the expression of the microtubule-destabilizing proteins stathmin and SCLIP eventually leading to increased motility of NSCLC (Singer et al., 2009).
Elevated expression of FUBP1 was also reported for renal cell and prostate carcinomas (Weber et al., 2008).
The oncogenic role of FUBP1 in hepatocellular carcinoma is discussed in the following note.
In contrast to the above described oncogenic role of FUBP1 in the majority of cancer entities it seems to function as a tumor suppressor in oligodendrogliomas, astrocytomas and oligoastrocytomas. In these cancer entities the FUBP1 locus is frequently mutated leading to inactivation of the protein (Bettegowda et al., 2011; Sahm et al., 2012; Jiao et al., 2012; Idbaih et al., 2012).
Entity name
Hepatocellular carcinoma
Note
FUBP1 is highly overexpressed in hepatocellular carcinoma. In HCC cells, knockdown of FUBP1 using stable shRNA (short hairpin RNA) expression resulted in increased apoptosis levels and decreased proliferation. In mouse xenograft experiments using these FUBP1-deficient HCC cells, tumor formation was impaired. Analysis of mRNA expression levels using quantitative real-time PCR revealed that c-myc expression was not influenced by knockdown of FUBP1, whereas several other so far unidentified target genes showed an altered expression pattern. The pro-apoptotic genes Bik, Noxa, TRAIL and TNF-α showed a reduced expression in the absence of FUBP1, whereas gene-expression of the cell cycle inhibitors p21 and p15 was increased. Cyclin D2 expression was also reduced in FUBP1 knockdown cells. Furthermore, p21 was identified as a direct FUBP1-target gene (Rabenhorst et al., 2009).
A decrease in tumor cell viability and proliferation was observed after siRNA mediated knockdown of FUBP1 in HCC cells. mRNA expression analysis revealed that FUBP1 induces the expression of the pro-tumorigenic microtubule-destabilizing protein stathmin (Malz et al., 2009). Elevated stathmin expression has been linked to vascular invasion, increased tumor size and intrahepatic metastasis in HCC (Yuan et al., 2006). Knockdown of FUBP2 resulted in elevated FUBP1 expression, indicating that FUBP family members are coodinately regulated. Based on these findings Malz et al. (2009) proposed that FUBP1 and FUBP2 support the migration and proliferation of human liver cancer cells.
Because of its regulatory effects on apoptosis, cell cycle progression and migration, FUBP1 fulfills an oncogenic potential, which seems to be of importance in hepatocellular carcinoma. A model of the oncogenic function of FUBP1 in HCC proposed by Rabenhorst et al. (2009) is shown in figure 2.
Atlas Image
Figure 2. Model of the oncogenic FUBP1 function in hepatocellular carcinoma. Increased levels of FUBP1 in HCC lead to decreased expression of the pro-apoptotic genes of Bik, Noxa, TRAIL and TNF-α. As a consequence, both, the intrinsic and extrinsic apoptosis pathway are inhibited. Moreover, FUBP1 decreases the gene expression of the cell cycle inhibitors p21 and p15, which leads to cell cycle acceleration. Taken from Rabenhorst et al., 2009.

Bibliography

Pubmed IDLast YearTitleAuthors
22117181990A far upstream element stimulates c-myc expression in undifferentiated leukemia cells.Avigan MI et al
77139311995Targeted melting and binding of a DNA regulatory element by a transactivator of c-myc.Bazar L et al
218170132011Mutations in CIC and FUBP1 contribute to human oligodendroglioma.Bettegowda C et al
118755762002Structure and dynamics of KH domains from FBP bound to single-stranded DNA.Braddock DT et al
199074342009The role of supercoiling in transcriptional control of MYC and its importance in molecular therapeutics.Brooks TA et al
169147412006FBPs are calibrated molecular tools to adjust gene expression.Chung HJ et al
89401891996The far upstream element-binding proteins comprise an ancient family of single-strand DNA-binding transactivators.Davis-Smyth T et al
81252591994A sequence-specific, single-strand binding protein activates the far upstream element of c-myc and defines a new DNA-binding motif.Duncan R et al
86282941996A unique transactivation sequence motif is found in the carboxyl-terminal domain of the single-strand-binding protein FBP.Duncan R et al
151751532004A KH domain RNA binding protein, KSRP, promotes ARE-directed mRNA turnover by recruiting the degradation machinery.Gherzi R et al
106989442000Loss of FBP function arrests cellular proliferation and extinguishes c-myc expression.He L et al
110719462000Nuclear targeting determinants of the far upstream element binding protein, a c-myc transcription factor.He L et al
204204262010Quantitative characterization of the interactions among c-myc transcriptional regulators FUSE, FBP, and FIR.Hsiao HH et al
230715312012SNP array analysis reveals novel genomic abnormalities including copy neutral loss of heterozygosity in anaplastic oligodendrogliomas.Idbaih A et al
90926401997Identification of two proteins that bind to a pyrimidine-rich sequence in the 3'-untranslated region of GAP-43 mRNA.Irwin N et al
228692052012Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.Jiao Y et al
35187461986The regulation and expression of c-myc in normal and malignant cells.Kelly K et al
155028472004The dynamic response of upstream DNA to transcription-generated torsional stress.Kouzine F et al
181930622008The functional response of upstream DNA to dynamic supercoiling in vivo.Kouzine F et al
112393932001Defective interplay of activators and repressors with TFIH in xeroderma pigmentosum.Liu J et al
108820742000The FBP interacting repressor targets TFIIH to inhibit activated transcription.Liu J et al
195856522009Overexpression of far upstream element binding proteins: a mechanism regulating proliferation and migration in liver cancer cells.Malz M et al
86493731996Multiple single-stranded cis elements are associated with activated chromatin of the human c-myc gene in vivo.Michelotti GA et al
91369301997A new regulatory protein, KSRP, mediates exon inclusion through an intronic splicing enhancer.Min H et al
208025332011Identification of FUSE-binding protein 1 as a regulatory mRNA-binding protein that represses nucleophosmin translation.Olanich ME et al
196371942009Overexpression of the far upstream element binding protein 1 in hepatocellular carcinoma is required for tumor growth.Rabenhorst U et al
225888992012CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas.Sahm F et al
192585022009Coordinated expression of stathmin family members by far upstream sequence element-binding protein-1 increases motility in non-small cell lung cancer.Singer S et al
84647041993The pre-mRNA binding K protein contains a novel evolutionarily conserved motif.Siomi H et al
150753902004A gene atlas of the mouse and human protein-encoding transcriptomes.Su AI et al
190873072008The FUSE binding proteins FBP1 and FBP3 are potential c-myc regulators in renal, but not in prostate and bladder cancer.Weber A et al
167390962006Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression, and is associated with tumour progression, early recurrence, and poor prognosis in hepatocellular carcinoma.Yuan RH et al
184008442008The FUSE binding protein is a cellular factor required for efficient replication of hepatitis C virus.Zhang Z et al
218556472011Far upstream element binding protein 1 activates translation of p27Kip1 mRNA through its internal ribosomal entry site.Zheng Y et al

Other Information

Locus ID:

NCBI: 8880
MIM: 603444
HGNC: 4004
Ensembl: ENSG00000162613

Variants:

dbSNP: 8880
ClinVar: 8880
TCGA: ENSG00000162613
COSMIC: FUBP1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000162613ENST00000294623Q96AE4
ENSG00000162613ENST00000294623A0A384MDX9
ENSG00000162613ENST00000370767E9PEB5
ENSG00000162613ENST00000370768Q96AE4
ENSG00000162613ENST00000421641C9JSZ1

Expression (GTEx)

0
10
20
30
40
50
60
70
80
90
100

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
228692052012Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.196
218170132011Mutations in CIC and FUBP1 contribute to human oligodendroglioma.177
166282152006The FUSE/FBP/FIR/TFIIH system is a molecular machine programming a pulse of c-myc expression.64
191655272009Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.56
225888992012CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas.48
217790032011USP22 regulates cell proliferation by deubiquitinating the transcriptional regulator FBP1.46
166722202006Identification of far upstream element-binding protein-1 as an authentic Parkin substrate.41
195856522009Overexpression of far upstream element binding proteins: a mechanism regulating proliferation and migration in liver cancer cells.39
229265192013Far upstream element binding protein 1: a commander of transcription, translation and beyond.39
196371942009Overexpression of the far upstream element binding protein 1 in hepatocellular carcinoma is required for tumor growth.38

Citation

Katharina Gerlach ; Martin Zörnig

FUBP1 (far upstream element (FUSE) binding protein 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-05-01

Online version: http://atlasgeneticsoncology.org/gene/50675/fubp1