Written | 2013-05 | Katharina Gerlach, Martin Zörnig |
Institute for Biomedical Research Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt, Germany |
Identity |
Alias (NCBI) | FBP | FUBP |
HGNC (Hugo) | FUBP1 |
HGNC Alias symb | FBP |
HGNC Alias name | FUSE binding protein 1 |
HGNC Previous name | FUBP |
HGNC Previous name | far upstream element (FUSE) binding protein 1 |
LocusID (NCBI) | 8880 |
Atlas_Id | 50675 |
Location | 1p31.1 [Link to chromosome band 1p31] |
Location_base_pair | Starts at 77948402 and ends at 77979205 bp from pter ( according to GRCh38/hg38-Dec_2013) [Mapping FUBP1.png] |
Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
FUBP1 (1p31.1) / CHMP1A (16q24.3) | FUBP1 (1p31.1) / ETV1 (7p21.2) | FUBP1 (1p31.1) / GPM6A (4q34.2) | |
FUBP1 (1p31.1) / IVNS1ABP (1q25.3) | FUBP1 (1p31.1) / LRRC7 (1p31.1) | FUBP1 (1p31.1) / SLC44A5 (1p31.1) | |
KHSRP (19p13.3) / FUBP1 (1p31.1) | SEC31A (4q21.22) / FUBP1 (1p31.1) |
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. |
Protein |
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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 |
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 |
Note | |
Entity | 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 | 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. |
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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 |
A far upstream element stimulates c-myc expression in undifferentiated leukemia cells. |
Avigan MI, Strober B, Levens D. |
J Biol Chem. 1990 Oct 25;265(30):18538-45. |
PMID 2211718 |
Targeted melting and binding of a DNA regulatory element by a transactivator of c-myc. |
Bazar L, Meighen D, Harris V, Duncan R, Levens D, Avigan M. |
J Biol Chem. 1995 Apr 7;270(14):8241-8. |
PMID 7713931 |
Mutations in CIC and FUBP1 contribute to human oligodendroglioma. |
Bettegowda C, Agrawal N, Jiao Y, Sausen M, Wood LD, Hruban RH, Rodriguez FJ, Cahill DP, McLendon R, Riggins G, Velculescu VE, Oba-Shinjo SM, Marie SK, Vogelstein B, Bigner D, Yan H, Papadopoulos N, Kinzler KW. |
Science. 2011 Sep 9;333(6048):1453-5. doi: 10.1126/science.1210557. Epub 2011 Aug 4. |
PMID 21817013 |
Structure and dynamics of KH domains from FBP bound to single-stranded DNA. |
Braddock DT, Louis JM, Baber JL, Levens D, Clore GM. |
Nature. 2002 Feb 28;415(6875):1051-6. |
PMID 11875576 |
The role of supercoiling in transcriptional control of MYC and its importance in molecular therapeutics. |
Brooks TA, Hurley LH. |
Nat Rev Cancer. 2009 Dec;9(12):849-61. doi: 10.1038/nrc2733. Epub 2009 Nov 12. (REVIEW) |
PMID 19907434 |
FBPs are calibrated molecular tools to adjust gene expression. |
Chung HJ, Liu J, Dundr M, Nie Z, Sanford S, Levens D. |
Mol Cell Biol. 2006 Sep;26(17):6584-97. |
PMID 16914741 |
The far upstream element-binding proteins comprise an ancient family of single-strand DNA-binding transactivators. |
Davis-Smyth T, Duncan RC, Zheng T, Michelotti G, Levens D. |
J Biol Chem. 1996 Dec 6;271(49):31679-87. |
PMID 8940189 |
A sequence-specific, single-strand binding protein activates the far upstream element of c-myc and defines a new DNA-binding motif. |
Duncan R, Bazar L, Michelotti G, Tomonaga T, Krutzsch H, Avigan M, Levens D. |
Genes Dev. 1994 Feb 15;8(4):465-80. |
PMID 8125259 |
A unique transactivation sequence motif is found in the carboxyl-terminal domain of the single-strand-binding protein FBP. |
Duncan R, Collins I, Tomonaga T, Zhang T, Levens D. |
Mol Cell Biol. 1996 May;16(5):2274-82. |
PMID 8628294 |
A KH domain RNA binding protein, KSRP, promotes ARE-directed mRNA turnover by recruiting the degradation machinery. |
Gherzi R, Lee KY, Briata P, Wegmuller D, Moroni C, Karin M, Chen CY. |
Mol Cell. 2004 Jun 4;14(5):571-83. |
PMID 15175153 |
Loss of FBP function arrests cellular proliferation and extinguishes c-myc expression. |
He L, Liu J, Collins I, Sanford S, O'Connell B, Benham CJ, Levens D. |
EMBO J. 2000a Mar 1;19(5):1034-44. |
PMID 10698944 |
Nuclear targeting determinants of the far upstream element binding protein, a c-myc transcription factor. |
He L, Weber A, Levens D. |
Nucleic Acids Res. 2000b Nov 15;28(22):4558-65. |
PMID 11071946 |
Quantitative characterization of the interactions among c-myc transcriptional regulators FUSE, FBP, and FIR. |
Hsiao HH, Nath A, Lin CY, Folta-Stogniew EJ, Rhoades E, Braddock DT. |
Biochemistry. 2010 Jun 8;49(22):4620-34. doi: 10.1021/bi9021445. |
PMID 20420426 |
SNP array analysis reveals novel genomic abnormalities including copy neutral loss of heterozygosity in anaplastic oligodendrogliomas. |
Idbaih A, Ducray F, Dehais C, Courdy C, Carpentier C, de Bernard S, Uro-Coste E, Mokhtari K, Jouvet A, Honnorat J, Chinot O, Ramirez C, Beauchesne P, Benouaich-Amiel A, Godard J, Eimer S, Parker F, Lechapt-Zalcman E, Colin P, Loussouarn D, Faillot T, Dam-Hieu P, Elouadhani-Hamdi S, Bauchet L, Langlois O, Le Guerinel C, Fontaine D, Vauleon E, Menei P, Fotso MJ, Desenclos C, Verrelle P, Ghiringhelli F, Noel G, Labrousse F, Carpentier A, Dhermain F, Delattre JY, Figarella-Branger D; POLA Network. |
PLoS One. 2012;7(10):e45950. doi: 10.1371/journal.pone.0045950. Epub 2012 Oct 10. |
PMID 23071531 |
Identification of two proteins that bind to a pyrimidine-rich sequence in the 3'-untranslated region of GAP-43 mRNA. |
Irwin N, Baekelandt V, Goritchenko L, Benowitz LI. |
Nucleic Acids Res. 1997 Mar 15;25(6):1281-8. |
PMID 9092640 |
Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. |
Jiao Y, Killela PJ, Reitman ZJ, Rasheed AB, Heaphy CM, de Wilde RF, Rodriguez FJ, Rosemberg S, Oba-Shinjo SM, Nagahashi Marie SK, Bettegowda C, Agrawal N, Lipp E, Pirozzi C, Lopez G, He Y, Friedman H, Friedman AH, Riggins GJ, Holdhoff M, Burger P, McLendon R, Bigner DD, Vogelstein B, Meeker AK, Kinzler KW, Papadopoulos N, Diaz LA, Yan H. |
Oncotarget. 2012 Jul;3(7):709-22. |
PMID 22869205 |
The regulation and expression of c-myc in normal and malignant cells. |
Kelly K, Siebenlist U. |
Annu Rev Immunol. 1986;4:317-38. (REVIEW) |
PMID 3518746 |
The dynamic response of upstream DNA to transcription-generated torsional stress. |
Kouzine F, Liu J, Sanford S, Chung HJ, Levens D. |
Nat Struct Mol Biol. 2004 Nov;11(11):1092-100. Epub 2004 Oct 24. |
PMID 15502847 |
The functional response of upstream DNA to dynamic supercoiling in vivo. |
Kouzine F, Sanford S, Elisha-Feil Z, Levens D. |
Nat Struct Mol Biol. 2008 Feb;15(2):146-54. doi: 10.1038/nsmb.1372. Epub 2008 Jan 13. |
PMID 18193062 |
Defective interplay of activators and repressors with TFIH in xeroderma pigmentosum. |
Liu J, Akoulitchev S, Weber A, Ge H, Chuikov S, Libutti D, Wang XW, Conaway JW, Harris CC, Conaway RC, Reinberg D, Levens D. |
Cell. 2001 Feb 9;104(3):353-63. |
PMID 11239393 |
The FBP interacting repressor targets TFIIH to inhibit activated transcription. |
Liu J, He L, Collins I, Ge H, Libutti D, Li J, Egly JM, Levens D. |
Mol Cell. 2000 Feb;5(2):331-41. |
PMID 10882074 |
Overexpression of far upstream element binding proteins: a mechanism regulating proliferation and migration in liver cancer cells. |
Malz M, Weber A, Singer S, Riehmer V, Bissinger M, Riener MO, Longerich T, Soll C, Vogel A, Angel P, Schirmacher P, Breuhahn K. |
Hepatology. 2009 Oct;50(4):1130-9. doi: 10.1002/hep.23051. |
PMID 19585652 |
Multiple single-stranded cis elements are associated with activated chromatin of the human c-myc gene in vivo. |
Michelotti GA, Michelotti EF, Pullner A, Duncan RC, Eick D, Levens D. |
Mol Cell Biol. 1996 Jun;16(6):2656-69. |
PMID 8649373 |
A new regulatory protein, KSRP, mediates exon inclusion through an intronic splicing enhancer. |
Min H, Turck CW, Nikolic JM, Black DL. |
Genes Dev. 1997 Apr 15;11(8):1023-36. |
PMID 9136930 |
Identification of FUSE-binding protein 1 as a regulatory mRNA-binding protein that represses nucleophosmin translation. |
Olanich ME, Moss BL, Piwnica-Worms D, Townsend RR, Weber JD. |
Oncogene. 2011 Jan 6;30(1):77-86. doi: 10.1038/onc.2010.404. Epub 2010 Aug 30. |
PMID 20802533 |
Overexpression of the far upstream element binding protein 1 in hepatocellular carcinoma is required for tumor growth. |
Rabenhorst U, Beinoraviciute-Kellner R, Brezniceanu ML, Joos S, Devens F, Lichter P, Rieker RJ, Trojan J, Chung HJ, Levens DL, Zornig M. |
Hepatology. 2009 Oct;50(4):1121-9. doi: 10.1002/hep.23098. |
PMID 19637194 |
CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas. |
Sahm F, Koelsche C, Meyer J, Pusch S, Lindenberg K, Mueller W, Herold-Mende C, von Deimling A, Hartmann C. |
Acta Neuropathol. 2012 Jun;123(6):853-60. doi: 10.1007/s00401-012-0993-5. Epub 2012 May 17. |
PMID 22588899 |
Coordinated expression of stathmin family members by far upstream sequence element-binding protein-1 increases motility in non-small cell lung cancer. |
Singer S, Malz M, Herpel E, Warth A, Bissinger M, Keith M, Muley T, Meister M, Hoffmann H, Penzel R, Gdynia G, Ehemann V, Schnabel PA, Kuner R, Huber P, Schirmacher P, Breuhahn K. |
Cancer Res. 2009 Mar 15;69(6):2234-43. doi: 10.1158/0008-5472.CAN-08-3338. Epub 2009 Mar 3. |
PMID 19258502 |
The pre-mRNA binding K protein contains a novel evolutionarily conserved motif. |
Siomi H, Matunis MJ, Michael WM, Dreyfuss G. |
Nucleic Acids Res. 1993 Mar 11;21(5):1193-8. |
PMID 8464704 |
A gene atlas of the mouse and human protein-encoding transcriptomes. |
Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, Zhang J, Soden R, Hayakawa M, Kreiman G, Cooke MP, Walker JR, Hogenesch JB. |
Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6062-7. Epub 2004 Apr 9. |
PMID 15075390 |
The FUSE binding proteins FBP1 and FBP3 are potential c-myc regulators in renal, but not in prostate and bladder cancer. |
Weber A, Kristiansen I, Johannsen M, Oelrich B, Scholmann K, Gunia S, May M, Meyer HA, Behnke S, Moch H, Kristiansen G. |
BMC Cancer. 2008 Dec 16;8:369. doi: 10.1186/1471-2407-8-369. |
PMID 19087307 |
Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression, and is associated with tumour progression, early recurrence, and poor prognosis in hepatocellular carcinoma. |
Yuan RH, Jeng YM, Chen HL, Lai PL, Pan HW, Hsieh FJ, Lin CY, Lee PH, Hsu HC. |
J Pathol. 2006 Aug;209(4):549-58. |
PMID 16739096 |
The FUSE binding protein is a cellular factor required for efficient replication of hepatitis C virus. |
Zhang Z, Harris D, Pandey VN. |
J Virol. 2008 Jun;82(12):5761-73. doi: 10.1128/JVI.00064-08. Epub 2008 Apr 9. |
PMID 18400844 |
Far upstream element binding protein 1 activates translation of p27Kip1 mRNA through its internal ribosomal entry site. |
Zheng Y, Miskimins WK. |
Int J Biochem Cell Biol. 2011 Nov;43(11):1641-8. doi: 10.1016/j.biocel.2011.08.001. Epub 2011 Aug 9. |
PMID 21855647 |
Citation |
This paper should be referenced as such : |
Gerlach, K ; Zörnig, M |
FUBP1 (far upstream element (FUSE) binding protein 1) |
Atlas Genet Cytogenet Oncol Haematol. 2013;17(12):816-820. |
Free journal version : [ pdf ] [ DOI ] |
Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 3 ] |
FUBP1/LRRC7 (1p31)
FUBP1/SLC44A5 (1p31) t(1;7)(p31;p21) FUBP1/ETV1 |
External links |
REVIEW articles | automatic search in PubMed |
Last year publications | automatic search in PubMed |
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