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FOXP1 (Forkhead box P1)

Identity

Other names12CC4
FLJ23741
hFKH1B
HSPC215
MGC12942
MGC88572
MGC9551
QRF1 (Glutamine-Rich Factor 1)
HGNC (Hugo) FOXP1
LocusID (NCBI) 27086
Location 3p13
Location_base_pair Starts at 71247034 and ends at 71633140 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order 3ptelomere-3' FOXP1 5'-centromere
 
  FOXP1 (3p14.1): RP11-154H23 (Spectrum0range) and RP11-79P21 (SpectrumGreen) covering the 5' and the 3'end of FOXP1, respectively.
Note chr3: 71087426-71715830 bps

DNA/RNA

Description 21 exons; the first 5 exons, the 5' part of exon 6 and the 3' part of exon 21 are non-coding.
Transcription 628405 bps mRNA; transcribed in a centromeric to telomeric orientation. Alternative splicing; 4 named isoforms (Q9H334-1,-2,-3,-4) recognized.

Protein

Note Forkhead box P1
 
  Schematic diagram of the Foxp1 protein indicating the localization of predicted domains and motifs. Modified from Banham AH et al., Cancer Res 61, 8820-8820, 2001.
Description The FOXP1 protein is 677-amino acid long and its molecular weight is 75317 Da. It contains two potential nucleic acid-binding motifs, including a forkhead (winged-helix) domain and C2H2 zinc finger domain. Other regions that may regulate transcription and mediate protein-protein interaction include coiled-coil, glutamine rich, S/T-rich, S/T/P-rich and acidic rich domains. Two potential nuclear localization signals (NLS) were identified at amino acid434-440 and amino acid543-546. Two potential PEST motifs are predicted in the acidic region near its COOH terminus. The FOXP1 protein contains a number potential of cyclin-cdk phosphorylation sites and a recognition site for the p70S6-kinase which is itself regulated by the PI(3)K. The FOXP1 protein forms homodimers and heterodimers with FOXP2 and FOXP4. Dimerization is required for DNA-binding.
Expression Ubiquitous expression in normal adult and fetal human tissues; highest expression in lymphoid and gastrointestinal tissues. Within the B lineage, FOXP1 is expressed modestly in progenitors, with highest levels in activated B cells and mantle zone B cells.
Localisation Predominantly nuclear
Function FOXP1 can act as a transcriptional repressor. The gene has a broad range of functions and plays an important role in cardiac and lung development, B-cell development and macrophage differentiation. FOXP1 is implicated in malignancy.
Homology Member of the broadly expressed FOXP subfamily which itself is a part of the FOX gene family of transcription factors, characterized by sharing a common DNA binding domain termed forkhead or a winged-helix domain. FOXP proteins (FOXP1, -2, -3, -4) play important roles in immune responses, organ development and cancer pathogenesis.

Implicated in

Entity t(3;9)(p14;p13) --> PAX5-FOXP1 in childhood ALL
Disease B-progenitor ALL (single case)
Cytogenetics Unknown
Abnormal Protein Contains the NH2 terminus of PAX5 with the DNA-binding paired, octapeptide and homeodomain-like domains and the COOH-terminus of FOXP1 containing its DNA-binding (Zn and FH) and transcriptional regulatory domains.
Oncogenesis The fusion protein is predicted to retain the ability to bind to PAX5 and FOXP1 transcriptional targets, but no longer provide normal transcriptional regulatory functions of both genes.
  
Entity t(3;14)(p14;q32)/B-cell malignancies IGH-FOXP1
Disease t(3;14)(p14;q32) resulting in upregulated expression of FOXP1, is a rare aberration in B-NHL. The translocation occurs recurrently in MALT-type of marginal zone B-cell lymphomas (MZBCL) and diffuse large B cell lymphoma (DLBCL). Single cases with variant FOXP1 translocations involving unknown non-IG loci have been reported.
Of note, a significant number of DLBCL (with a predominantly ABC-like phenotype) and extranodal MZBCL displayed a strong expression of FOXP1 which is independent of genomic rearrangements of the FOXP1 locus. FOXP1-positivity was also found in numerous cases of cutaneous B-cell lymphomas and follicular lymphomas.
Prognosis High expression of FOXP1 in DLBCL is associated with poor prognosis. Deregulation of FOXP1 in MALT lymphomas possibly leads to transformation to a more aggressive DLBCL.
Cytogenetics t(3;14) was recorded as a sole aberration and as a part of complex karyotypes. In MALT lymphomas, translocations involving FOXP1, MALT1 and BCL10 are mutually exclusive.
Hybrid/Mutated Gene No hybrid gene; 5' FOXP1 juxtaposed with 3' IGH enhancer. Molecular characteristics of FOXP1 variant translocations are unknown.
Oncogenesis The occurrence of activated FOXP1 translocations in lymphoma indicates that FOXP1 functions as an oncogene. So far, mechanisms and molecular consequences of aberrant expression of FOXP1 in lymphomas not harboring 3p14/FOXP1 rearrangements are unknown. The preliminary data suggest that not the full-length protein, but smaller FOXP1 isoforms are atypically highly expressed in ABC-DLBCL cell lines. Their role in the disease process is currently investigated.
  
Entity Solid tumors
Disease FOXP1 abnormalities (overexpression, mislocalization or loss of FOXP1) are observed in a wide variety of cancers, particularly of epithelial origin.
FOXP1 located in the 3p region frequently deleted in multiple types of cancers is one of a few potential tumor suppressor genes. Genomic loss of FOXP1 correlates with a decrease in FOXP1 mRNA and/or a decrease in FOXP1 protein levels in a significant number of analyzed lung cancers and head and neck cancers. In addition, an aberrant cytoplasmic localization of FOXP1 has been observed in a number of epithelial malignancies. Whether that aberrant localization may be a mechanism for inactivation of FOXP1 remains to be determined. So far, the direct evidence that FOXP1 functions as a tumor suppressor gene is limited.
In contrast, increased nuclear expression of FOXP1 has been detected in renal cell carcinoma, some prostate cancers, endometrial cancers and breast cancers. The mechanisms leading to altered expression of FOXP1 in cancer are elusive.
  

Breakpoints

 
 
  Recurrent (14q32/IGH) and non-recurrent chromosomal breakpoints/partners involved in the FOXP1 rearrangements in hematological malignancies.

Other Leukemias implicated (Data extracted from papers in the Atlas)

Leukemias 11q23ChildAMLID1615 11q23ID1030 11q23secondLeukID1131 t1119ELLID1029

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors AmeloblastomID5945

External links

Nomenclature
HGNC (Hugo)FOXP1   3823
Cards
AtlasFOXP1ID40632ch3p14
Entrez_Gene (NCBI)FOXP1  27086  forkhead box P1
GeneCards (Weizmann)FOXP1
Ensembl (Hinxton)ENSG00000114861 [Gene_View]  chr3:71247034-71633140 [Contig_View]  FOXP1 [Vega]
ICGC DataPortalENSG00000114861
AceView (NCBI)FOXP1
Genatlas (Paris)FOXP1
WikiGenes27086
SOURCE (Princeton)NM_001012505 NM_001244808 NM_001244810 NM_001244812 NM_001244813 NM_001244814 NM_001244815 NM_001244816 NM_032682
Genomic and cartography
GoldenPath (UCSC)FOXP1  -  3p13   chr3:71247034-71633140 -  3p14.1   [Description]    (hg19-Feb_2009)
EnsemblFOXP1 - 3p14.1 [CytoView]
Mapping of homologs : NCBIFOXP1 [Mapview]
OMIM605515   613670   
Gene and transcription
Genbank (Entrez)AA380962 AB052767 AF146696 AF151049 AF250920
RefSeq transcript (Entrez)NM_001012505 NM_001244808 NM_001244810 NM_001244812 NM_001244813 NM_001244814 NM_001244815 NM_001244816 NM_032682
RefSeq genomic (Entrez)AC_000135 NC_000003 NC_018914 NG_028243 NT_022517 NW_001838878 NW_004929310
Consensus coding sequences : CCDS (NCBI)FOXP1
Cluster EST : UnigeneHs.59368 [ NCBI ]
CGAP (NCI)Hs.59368
Alternative Splicing : Fast-db (Paris)GSHG0021849
Alternative Splicing GalleryENSG00000114861
Gene ExpressionFOXP1 [ NCBI-GEO ]     FOXP1 [ SEEK ]   FOXP1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9H334 (Uniprot)
NextProtQ9H334  [Medical]
With graphics : InterProQ9H334
Splice isoforms : SwissVarQ9H334 (Swissvar)
Domaine pattern : Prosite (Expaxy)FORK_HEAD_2 (PS00658)    FORK_HEAD_3 (PS50039)    ZINC_FINGER_C2H2_1 (PS00028)   
Domains : Interpro (EBI)TF_fork_head    TF_fork_head_CS    WHTH_DNA-bd_dom    Znf_C2H2-like   
Related proteins : CluSTrQ9H334
Domain families : Pfam (Sanger)Fork_head (PF00250)   
Domain families : Pfam (NCBI)pfam00250   
Domain families : Smart (EMBL)FH (SM00339)  ZnF_C2H2 (SM00355)  
DMDM Disease mutations27086
Blocks (Seattle)Q9H334
PDB (SRS)2KIU   
PDB (PDBSum)2KIU   
PDB (IMB)2KIU   
PDB (RSDB)2KIU   
Human Protein AtlasENSG00000114861
Peptide AtlasQ9H334
HPRD18518
IPIIPI00023098   IPI00220201   IPI00748383   IPI00166439   IPI00947112   IPI00946520   IPI00182980   IPI00220203   IPI00947506   IPI00013412   IPI00947347   
Protein Interaction databases
DIP (DOE-UCLA)Q9H334
IntAct (EBI)Q9H334
FunCoupENSG00000114861
BioGRIDFOXP1
IntegromeDBFOXP1
STRING (EMBL)FOXP1
Ontologies - Pathways
QuickGOQ9H334
Ontology : AmiGOsequence-specific DNA binding transcription factor activity  nucleus  nucleolus  transcription, DNA-templated  sequence-specific DNA binding  negative regulation of transcription, DNA-templated  metal ion binding  
Ontology : EGO-EBIsequence-specific DNA binding transcription factor activity  nucleus  nucleolus  transcription, DNA-templated  sequence-specific DNA binding  negative regulation of transcription, DNA-templated  metal ion binding  
Pathways : KEGGMicroRNAs in cancer   
Protein Interaction DatabaseFOXP1
Wikipedia pathwaysFOXP1
Gene fusion - rearrangments
Rearrangement : TICdbFOXP1 [3p13]  -  ABL1 [3q28]
Rearrangement : TICdb- [-]  -  FOXP1 [10p12.1]
Rearrangement : TICdbPAX5 [9p13.2]  -  FOXP1 [-]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)FOXP1
SNP (GeneSNP Utah)FOXP1
SNP : HGBaseFOXP1
Genetic variants : HAPMAPFOXP1
1000_GenomesFOXP1 
ICGC programENSG00000114861 
Cancer Gene: CensusFOXP1 
CONAN: Copy Number AnalysisFOXP1 
Somatic Mutations in Cancer : COSMICFOXP1 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
DECIPHER (Syndromes)3:71247034-71633140
Mutations and Diseases : HGMDFOXP1
OMIM605515    613670   
MedgenFOXP1
GENETestsFOXP1
Disease Genetic AssociationFOXP1
Huge Navigator FOXP1 [HugePedia]  FOXP1 [HugeCancerGEM]
Genomic VariantsFOXP1  FOXP1 [DGVbeta]
Exome VariantFOXP1
dbVarFOXP1
ClinVarFOXP1
snp3D : Map Gene to Disease27086
General knowledge
Homologs : HomoloGeneFOXP1
Homology/Alignments : Family Browser (UCSC)FOXP1
Phylogenetic Trees/Animal Genes : TreeFamFOXP1
Chemical/Protein Interactions : CTD27086
Chemical/Pharm GKB GenePA28241
Clinical trialFOXP1
Cancer Resource (Charite)ENSG00000114861
Other databases
Probes
Litterature
PubMed98 Pubmed reference(s) in Entrez
CoreMineFOXP1
GoPubMedFOXP1
iHOPFOXP1

Bibliography

DNA-binding properties and secondary structural model of the hepatocyte nuclear factor 3/fork head domain.
Li C, Tucker PW
Proceedings of the National Academy of Sciences of the United States of America. 1993 ; 90 (24) : 11583-11587.
PMID 8265594
 
The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p.
Banham AH, Beasley N, Campo E, Fernandez PL, Fidler C, Gatter K, Jones M, Mason DY, Prime JE, Trougouboff P, Wood K, Cordell JL
Cancer research. 2001 ; 61 (24) : 8820-8829.
PMID 11751404
 
Forkhead transcription factors: key players in development and metabolism.
Carlsson P, Mahlapuu M
Developmental biology. 2002 ; 250 (1) : 1-23.
PMID 12297093
 
Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional repressors.
Wang B, Lin D, Li C, Tucker P
The Journal of biological chemistry. 2003 ; 278 (27) : 24259-24268.
PMID 12692134
 
Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome.
Barrans SL, Fenton JA, Banham A, Owen RG, Jack AS
Blood. 2004 ; 104 (9) : 2933-2935.
PMID 15238418
 
Expression of the forkhead transcription factor FOXP1 is associated with estrogen receptor alpha and improved survival in primary human breast carcinomas.
Fox SB, Brown P, Han C, Ashe S, Leek RD, Harris AL, Banham AH
Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 ; 10 (10) : 3521-3527.
PMID 15161711
 
Human FOX gene family (Review).
Katoh M, Katoh M
International journal of oncology. 2004 ; 25 (5) : 1495-1500.
PMID 15492844
 
Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1.
Shi C, Zhang X, Chen Z, Sulaiman K, Feinberg MW, Ballantyne CM, Jain MK, Simon DI
The Journal of clinical investigation. 2004 ; 114 (3) : 408-418.
PMID 15286807
 
Foxp1 regulates cardiac outflow tract, endocardial cushion morphogenesis and myocyte proliferation and maturation.
Wang B, Weidenfeld J, Lu MM, Maika S, Kuziel WA, Morrisey EE, Tucker PW
Development (Cambridge, England). 2004 ; 131 (18) : 4477-4487.
PMID 15342473
 
Expression of the FOXP1 transcription factor is strongly associated with inferior survival in patients with diffuse large B-cell lymphoma.
Banham AH, Connors JM, Brown PJ, Cordell JL, Ott G, Sreenivasan G, Farinha P, Horsman DE, Gascoyne RD
Clinical cancer research : an official journal of the American Association for Cancer Research. 2005 ; 11 (3) : 1065-1072.
PMID 15709173
 
The FOXP1 transcription factor is expressed in the majority of follicular lymphomas but is rarely expressed in classical and lymphocyte predominant Hodgkin's lymphoma.
Brown P, Marafioti T, Kusec R, Banham AH
Journal of molecular histology. 2005 ; 36 (4) : 249-256.
PMID 16200457
 
T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma.
Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2005 ; 19 (4) : 652-658.
PMID 15703784
 
FOXP1, a gene highly expressed in a subset of diffuse large B-cell lymphoma, is recurrently targeted by genomic aberrations.
Wlodarska I, Veyt E, De Paepe P, Vandenberghe P, Nooijen P, Theate I, Michaux L, Sagaert X, Marynen P, Hagemeijer A, De Wolf-Peeters C
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2005 ; 19 (8) : 1299-1305.
PMID 15944719
 
t(3;14)(p14;q32) results in aberrant expression of FOXP1 in a case of diffuse large B-cell lymphoma.
Fenton JA, Schuuring E, Barrans SL, Banham AH, Rollinson SJ, Morgan GJ, Jack AS, van Krieken JH, Kluin PM
Genes, chromosomes & cancer. 2006 ; 45 (2) : 164-168.
PMID 16252263
 
Loss of expression and nuclear/cytoplasmic localization of the FOXP1 forkhead transcription factor are common events in early endometrial cancer: relationship with estrogen receptors and HIF-1alpha expression.
Giatromanolaki A, Koukourakis MI, Sivridis E, Gatter KC, Harris AL, Banham AH
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2006 ; 19 (1) : 9-16.
PMID 16258506
 
Genetic rearrangement of FOXP1 is predominantly detected in a subset of diffuse large B-cell lymphomas with extranodal presentation.
Haralambieva E, Adam P, Ventura R, Katzenberger T, Kalla J, Hller S, Hartmann M, Rosenwald A, Greiner A, Muller-Hermelink HK, Banham AH, Ott G
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2006 ; 20 (7) : 1300-1303.
PMID 16673020
 
Foxp1 is an essential transcriptional regulator of B cell development.
Hu H, Wang B, Borde M, Nardone J, Maika S, Allred L, Tucker PW, Rao A
Nature immunology. 2006 ; 7 (8) : 819-826.
PMID 16819554
 
Forkhead box protein P1 expression in mucosa-associated lymphoid tissue lymphomas predicts poor prognosis and transformation to diffuse large B-cell lymphoma.
Sagaert X, de Paepe P, Libbrecht L, Vanhentenrijk V, Verhoef G, Thomas J, Wlodarska I, De Wolf-Peeters C
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006 ; 24 (16) : 2490-2497.
PMID 16636337
 
Reduced expressions of Foxp1 and Rassf1a genes in lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine in rats.
Shimizu K, Kato A, Hinotsume D, Shigemura M, Hanaoka M, Shimoichi Y, Honoki K, Tsujiuchi T
Cancer letters. 2006 ; 236 (2) : 186-190.
PMID 16023287
 
Expression of the forkhead transcription factor FOXP1 is associated both with hypoxia inducible factors (HIFs) and the androgen receptor in prostate cancer but is not directly regulated by androgens or hypoxia.
Banham AH, Boddy J, Launchbury R, Han C, Turley H, Malone PR, Harris AL, Fox SB
The Prostate. 2007 ; 67 (10) : 1091-1098.
PMID 17477366
 
FOXP1: a potential therapeutic target in cancer.
Koon HB, Ippolito GC, Banham AH, Tucker PW
Expert opinion on therapeutic targets. 2007 ; 11 (7) : 955-965.
PMID 17614763
 
Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.
Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, Girtman K, Mathew S, Ma J, Pounds SB, Su X, Pui CH, Relling MV, Evans WE, Shurtleff SA, Downing JR
Nature. 2007 ; 446 (7137) : 758-764.
PMID 17344859
 
REVIEW articlesautomatic search in PubMed
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Contributor(s)

Written08-2007Iwona Wlodarska
Department of Human Genetics, Catholic University Leuven, Leuven, Belgium

Citation

This paper should be referenced as such :
Wlodarska, I
FOXP1 (forkhead box P1)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2):100-103.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/FOXP1ID40632ch3p14.html

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indexed on : Sat Nov 8 16:47:20 CET 2014

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