FOXP1 (Forkhead box P1)

2007-08-01   Iwona Wlodarska 

Department of Human Genetics, Catholic University Leuven, Leuven, Belgium

Identity

HGNC
LOCATION
3p13
IMAGE
Atlas Image
LEGEND
FOXP1 (3p14.1): RP11-154H23 (Spectrum0range) and RP11-79P21 (SpectrumGreen) covering the 5 and the 3end of FOXP1, respectively.
LOCUSID
ALIAS
12CC4,HSPC215,MFH,QRF1,hFKH1B
FUSION GENES

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.

Proteins

Note

Forkhead box P1
Atlas Image
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 name
t(3;9)(p14;p13) --> PAX5-FOXP1 in childhood ALL
Disease
B-progenitor ALL (single case)
Cytogenetics
Unknown
Fusion 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 name
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 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 name
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

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

Bibliography

Pubmed IDLast YearTitleAuthors
174773662007Expression 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 et al
157091732005Expression of the FOXP1 transcription factor is strongly associated with inferior survival in patients with diffuse large B-cell lymphoma.Banham AH et al
152384182004Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome.Barrans SL et al
162004572005The 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 et al
122970932002Forkhead transcription factors: key players in development and metabolism.Carlsson P et al
162522632006t(3;14)(p14;q32) results in aberrant expression of FOXP1 in a case of diffuse large B-cell lymphoma.Fenton JA et al
151617112004Expression of the forkhead transcription factor FOXP1 is associated with estrogen receptor alpha and improved survival in primary human breast carcinomas.Fox SB et al
162585062006Loss 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 et al
166730202006Genetic rearrangement of FOXP1 is predominantly detected in a subset of diffuse large B-cell lymphomas with extranodal presentation.Haralambieva E et al
168195542006Foxp1 is an essential transcriptional regulator of B cell development.Hu H et al
154928442004Human FOX gene family (Review).Katoh M et al
176147632007FOXP1: a potential therapeutic target in cancer.Koon HB et al
82655941993DNA-binding properties and secondary structural model of the hepatocyte nuclear factor 3/fork head domain.Li C et al
173448592007Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.Mullighan CG et al
166363372006Forkhead box protein P1 expression in mucosa-associated lymphoid tissue lymphomas predicts poor prognosis and transformation to diffuse large B-cell lymphoma.Sagaert X et al
152868072004Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1.Shi C et al
160232872006Reduced expressions of Foxp1 and Rassf1a genes in lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine in rats.Shimizu K et al
157037842005T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma.Streubel B et al
126921342003Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional repressors.Wang B et al
153424732004Foxp1 regulates cardiac outflow tract, endocardial cushion morphogenesis and myocyte proliferation and maturation.Wang B et al
159447192005FOXP1, a gene highly expressed in a subset of diffuse large B-cell lymphoma, is recurrently targeted by genomic aberrations.Wlodarska I et al

Other Information

Locus ID:

NCBI: 27086
MIM: 605515
HGNC: 3823
Ensembl: ENSG00000114861

Variants:

dbSNP: 27086
ClinVar: 27086
TCGA: ENSG00000114861
COSMIC: FOXP1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000114861ENST00000318779Q9H334
ENSG00000114861ENST00000318789Q9H334
ENSG00000114861ENST00000318789Q548T7
ENSG00000114861ENST00000327590G5E965
ENSG00000114861ENST00000468577C9J0F0
ENSG00000114861ENST00000471386A0A3B3ITZ4
ENSG00000114861ENST00000472382A0A087X2G3
ENSG00000114861ENST00000475937Q9H334
ENSG00000114861ENST00000475937Q548T7
ENSG00000114861ENST00000484350Q9H334
ENSG00000114861ENST00000485326C9J5T4
ENSG00000114861ENST00000493089Q9H334
ENSG00000114861ENST00000497355H0Y882
ENSG00000114861ENST00000497553C9IYY1
ENSG00000114861ENST00000498215Q9H334
ENSG00000114861ENST00000498215Q548T7
ENSG00000114861ENST00000610810A0A087WVT2
ENSG00000114861ENST00000614176A0A0B4J2F3
ENSG00000114861ENST00000615603Q9H334
ENSG00000114861ENST00000622151Q9H334
ENSG00000114861ENST00000647614A0A3B3IT26
ENSG00000114861ENST00000648107Q9H334
ENSG00000114861ENST00000648121A0A3B3ISQ6
ENSG00000114861ENST00000648321A0A3B3IU15
ENSG00000114861ENST00000648380Q9H334
ENSG00000114861ENST00000648380Q548T7
ENSG00000114861ENST00000648384A0A3B3IU08
ENSG00000114861ENST00000648426Q9H334
ENSG00000114861ENST00000648654A0A3B3ISA4
ENSG00000114861ENST00000648662Q9H334
ENSG00000114861ENST00000648710A0A3B3IST0
ENSG00000114861ENST00000648718Q9H334
ENSG00000114861ENST00000648748A0A3B3IS20
ENSG00000114861ENST00000648783A0A3B3ITZ4
ENSG00000114861ENST00000648794A0A0B4J2F3
ENSG00000114861ENST00000648895A0A3B3ISQ7
ENSG00000114861ENST00000648944A0A3B3ISQ3
ENSG00000114861ENST00000649431A0A3B3IUB6
ENSG00000114861ENST00000649513A0A3B3IS87
ENSG00000114861ENST00000649528Q9H334
ENSG00000114861ENST00000649528Q548T7
ENSG00000114861ENST00000649592A0A3B3IT66
ENSG00000114861ENST00000649596A0A3B3IRS5
ENSG00000114861ENST00000649610A0A3B3IRS5
ENSG00000114861ENST00000649631Q9H334
ENSG00000114861ENST00000649631Q548T7
ENSG00000114861ENST00000649695Q9H334
ENSG00000114861ENST00000650068A0A3B3IST6
ENSG00000114861ENST00000650156A0A3B3IRL7
ENSG00000114861ENST00000650188A0A3B3IRW5
ENSG00000114861ENST00000650295A0A3B3IRY1
ENSG00000114861ENST00000650387A0A3B3IT66
ENSG00000114861ENST00000650402A0A3B3IT14

Expression (GTEx)

0
5
10
15
20
25
30
35

Pathways

PathwaySourceExternal ID
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Developmental BiologyREACTOMER-HSA-1266738
Transcriptional regulation of pluripotent stem cellsREACTOMER-HSA-452723

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA447199Bipolar DisorderDiseaseLiterature, MultilinkAnnotationassociated24718920

References

Pubmed IDYearTitleCitations
219247632011An alternative splicing switch regulates embryonic stem cell pluripotency and reprogramming.135
150566952004Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction.115
147017522004Transcriptional and DNA binding activity of the Foxp1/2/4 family is modulated by heterotypic and homotypic protein interactions.108
169529802006Transcriptional genomics associates FOX transcription factors with human heart failure.89
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
209507882010De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment.79
117514042001The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p.71
157037842005T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma.65
126921342003Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional repressors.64
214602422011Myc-mediated repression of microRNA-34a promotes high-grade transformation of B-cell lymphoma by dysregulation of FoxP1.63

Citation

Iwona Wlodarska

FOXP1 (Forkhead box P1)

Atlas Genet Cytogenet Oncol Haematol. 2007-08-01

Online version: http://atlasgeneticsoncology.org/gene/40632/foxp1