Download Gene Section FOXF1 (forkhead box F1) Atlas of Genetics and Cytogenetics

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Gene Section
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FOXF1 (forkhead box F1)
Pang-Kuo Lo
Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208, USA
(PKL)
Published in Atlas Database: February 2012
Online updated version : http://AtlasGeneticsOncology.org/Genes/FOXF1ID40628ch16q24.html
DOI: 10.4267/2042/47416
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
forkhead family which is characterized by a unique
forkhead DNA-binding domain. The function of this
gene is implicated in regulation of embryonic
development and organ morphogenesis.
The cellular role of this gene has been found to regulate
cell cycle progression and epithelial-to-mesenchymal
transition (EMT).
Dysregulation of FOXF1 gene expression has been
linked to various cancers and genomic deletions or
mutations at this gene locus have been discovered to be
associated with congenital abnormalities.
The role of FOXF1 in cancer has been proposed to act
as either an oncogene or a tumor suppressor gene
depending on cell types and disease stages.
Identity
Other names: ACDMPV, FKHL5, FREAC1
HGNC (Hugo): FOXF1
Location: 16q24.1
Local order:
According to the NCBI Map Viewer, genes flanking
FOXF1 in centromere to telomere direction on 16q24
are:
- LOC401864 (chloride intracellular channel 1
pseudogene);
- FLJ34515 (uncharacterized LOC400550);
- FOXF1 (forkhead box F1);
- RPL7AP63 (ribosomal protein L7a pseudogene 63);
- MTHFSD (methenyltetrahydrofolate synthetase
domain containing);
- FLJ30679 (uncharacterized protein FLJ30679);
- FOXC2 (forkhead box C2, mesenchyme forkhead 1);
- FOXL1 (forkhead box L1).
Note
This gene encodes a transcription factor of the
DNA/RNA
Description
The FOXF1 gene is composed of two exons with sizes
of 1022 and 1540 bp, respectively.
Transcription
The FOXF1 gene expresses 2,58 kb mRNA with the
1140 bp open reading frame.
The pink boxes indicate the open reading frame and the sky blue boxes indicate the untranslated mRNA region.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7)
467
FOXF1 (forkhead box F1)
Lo PK
progression and is almost absent from lymph node
metastases (Nilsson et al., 2010). FOXF1 is
preferentially expressed in breast cancer cell lines with
a mesenchymal phenotype and its ectopic
overexpression in mammary epithelial cells induces
mesenchymal traits, increased invasiveness in vitro and
enhanced xenograft tumorigenesis in vivo (Nilsson et
al., 2010). Hence FOXF1 is proposed to promote
invasion and metastasis.
The oncogenic role of FOXF1 in lung cancerassociated fibroblasts: FOXF1 is found to be
expressed in cancer-associated fibroblasts of human
lung cancer and associated with activation of hedgehog
signaling (Saito et al., 2010). Gain- and loss-offunction studies of FOXF1 in fibroblasts show that
FOXF1 is implicated in regulating the contractility of
fibroblasts and abilities of fibroblasts to produce
hepatocyte growth factor as well as fibroblast growth
factor-2 and to stimulate migration of lung cancer
epithelial cells (Saito et al., 2010). The expression
status of FOXF1 in fibroblasts positively correlates
with the ability of fibroblasts to enhance xenograft
tumor growth (Saito et al., 2010). These findings
suggest that hedgehog-dependent FOXF1 is a clinically
relevant factor to grant oncogenic abilities to cancerassociated fibroblasts for propelling development of
lung cancer.
The role of FOXF1 in regulation of cell cycle
progression: FOXF1 has been identified as a target of
epigenetic inactivation in breast cancer (Lo et al.,
2010). Ectopic reexpression of FOXF1 in FOXF1negative breast cancer cells induces cell growth arrest
by inhibition of the CDK2-RB-E2F cascade (Lo et al.,
2010). FOXF1 knockdown studies of FOXF1expressing breast cancer epithelial cells revealed that
FOXF1 is indispensable for maintaining the stringency
of DNA replication and genomic stability by negatively
modulating expression of E2F target genes which are
involved in promoting the progression of S and G2
phases (Lo et al., 2010; Lo et al., 2012). These lines of
evidence suggest that FOXF1 is an epigenetically
silenced tumor suppressor gene in breast cancer, which
is essential for maintaining genomic stability by
regulating the stringency of DNA replication.
Protein
Description
Human FOXF1 is a 379 amino acid protein functioning
as a transcription factor. The FOXF1 protein contains a
forkhead domain (or called winged helix, 48-125 amino
acids) engaged in binding to B-DNA (Kim et al., 2005).
According to the information from the NCBI reference
sequence NP_001442 for the FOXF1 protein, amino
acids 84, 85, 94, 97, 98 and 118 are involved in
interaction with nucleotides of DNA. In addition to the
forkhead DNA-binding domain, the C-terminal of
FOXF1 possesses characteristics of the transcriptional
activation domain (Mahlapuu et al., 1998). However,
its region has not yet been convincingly defined. The
studies have shown that FOXF1 transcripitionally
modulates expression of tissue-specific genes (e.g.
lung, intestine) (Hellqvist et al., 1996; Mahlapuu et al.,
1998; Costa et al., 2001; Ormestad et al., 2006;
Madison et al., 2009).
Expression
According to published literature, the FOXF1
transcription factor has been identified to be highly
expressed in the normal human prostate transition zone
and benign prostate hyperplasia (BPH), but
decreasingly expressed in prostate cancer (Watson et
al., 2004; van der Heul-Nieuwenhuijsen et al., 2009).
FOXF1 is expressed in normal breast ductal epithelial
cells and basal-like breast cancer cells, but is silenced
in luminal breast cancer cells mainly through the
epigenetic mechanism (Lo et al., 2010; Nilsson et al.,
2010). FOXF1 expression is detected in cancerassociated fibroblasts of human lung cancer and its
expression is associated with activation of hedgehog
signaling (Saito et al., 2010). Upregulation of FOXF1
expression is also found in PTCH1-associated
rhabdomyosarcoma (Wendling et al., 2008).
Localisation
Localized in the nucleus.
Function
The biological roles of forkhead box protein F1 were
mostly studied in murine genetic models and are linked
to regulate embryogenesis and organogenesis
(Mahlapuu et al., 2001a; Costa et al., 2001;
Kalinichenko et al., 2001; Mahlapuu et al., 2001b;
Kalinichenko et al., 2002; Lim et al., 2002; Ormestad et
al., 2006; Astorga and Carlsson, 2007; Yu et al., 2010).
However, the functional roles of the human FOXF1
protein are still largely unknown. Some of published
studies indicate that FOXF1 participates in regulation
of the following normal and abnormal cellular
processes:
The role of FOXF1 in an Epithelial-to-Mesenchymal
Transition (EMT): FOXF1 has been found to be a
direct repressed target of nuclear factor 1-C2 (NF1-C2)
whose expression is lost during mammary tumor
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7)
Homology
Pan
troglodytes
(chimpanzee),
FOXF1
(XP_523449.2, 535 aa), 99% identity;
- Canis lupus (dog), FOXF1 (XP_546792.2, 354 aa),
95% identity;
- Bos taurus (cattle), FOXF1 (XP_603148.3, 382 aa),
96% identity;
- Mus musculus (mouse), Foxf1a (NP_034556.1, 353
aa), 94% identity;
- Gallus gallus (chicken), FOXF1 (XP_414186.2, 368
aa), 91% identity;
- Danio rerio (zebrafish), Foxf1 (NP_001073655.1, 380
aa), 81% identity.
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FOXF1 (forkhead box F1)
Lo PK
Prostate cancer
Mutations
Oncogenesis
FOXF1 expression is lost or downregulated in prostate
cancer compared with normal prostate tissue (Watson
et al., 2004; van der Heul-Nieuwenhuijsen et al., 2009).
This suggests that FOXF1 is a putative tumor
suppressor gene in prostate cancer.
Note
Four different heterozygous mutations (frameshift,
nonsense, and non-stop) have been identified in the
FOXF1 gene in unrelated patients with sporadic
ACD/MPV (alveolar capillary dysplasia with
misalignment of pulmonary veins) and MCA (multiple
congenital anomalies) (Stankiewicz et al., 2009). The
point mutations identified in the FOXF1 gene are
associated with bowel malrotation, annular pancreas,
duodenal stenosis, congenital short bowel, small
omphalocele and Meckel's diverticulum (Stankiewicz
et al., 2009).
Nevoid basal cell carcinoma syndrome
Disease
Patients with nevoid basal cell carcinoma syndrome
(NBCCS) carry germline mutation in the tumor
suppressor gene Patched 1 (PTCH1) and are
predisposed to develop basal cell carcinoma (BCC),
medulloblastoma (MB) and rhabdomyosarcoma
(RMS).
Oncogenesis
FOXF1 expression is found to be aberrantly
upregulated in NBCCS-associated tumors compared
with the respective non-neoplastic tissue (Wendling et
al., 2008). Overexpression of FOXF1 is accompanied
by increased levels of the hedgehog target Gli1 as well
as the putative FOXF1 targets Bmi1 and Notch2 in
NBCCS-associated tumors (Wendling et al., 2008).
These findings suggest a key role for FOXF1 in
hedgehog-associated tumorigenesis.
Implicated in
Breast cancer
Oncogenesis
Loss or downregulation of FOXF1 expression is found
to
be
associated
with
FOXF1
promoter
hypermethylation in breast cancer cell lines and in
breast invasive ductal carcinomas (Lo et al., 2010).
According to analysis of 117 invasive ductal carcinoma
(IDC) cases, FOXF1 promoter was hypermethylated in
37,6% of examined IDC cases, which was associated
with high tumor grade (Lo et al., 2010). The gain- and
loss-of-function studies of FOXF1 in breast cancer
cells indicate that FOXF1 plays an imperative role in
maintaining the stringency of DNA replication for
sustaining genomic stability (Lo et al., 2010; Lo et al.,
2012). These clinical correlation and cellular functional
studies suggest that FOXF1 is a potential tumor
suppressor gene which is epigenetically silenced in
breast cancer.
Idiopathic interstitial pneumonias
Disease
The idiopathic interstitial pneumonias (IIP) represent a
set of diffuse parenchymal lung disorders and are subclassified into usual interstitial pneumonitis (UIP),
nonspecific interstitial pneumonitis (NSIP) and the
fibrotic variant of NSIP (NSIP-F).
Examination of surgical and autopsy specimens from
13 patients with either UIP or NSIP-F has revealed that
all of UIP cases exhibited a pattern of strong SHH (a
hedgehog ligand) expression with weak FOXF1
expression and NSIP-F cases displayed a
complementary expression of SHH and FOXF1 (Coon
et al., 2006). These studies suggest that morphogenetic
genes (e.g. FOXF1) may participate differentially in the
pathogenesis of UIP and NSIP-F.
Lung cancer
Oncogenesis
Immunohistochemical (IHC) staining of FOXF1 is
found to be positive in nuclei of lung cancer-associated
fibroblasts (CAFs) (Saito et al., 2010). The frequency
of positivity of FOXF1 IHC staining in CAFs is 110
(44,5%) out of 247 cases examined (Saito et al., 2010).
The IHC studies exhibited stronger FOXF1 staining in
the stromal cells adjacent to lung tumor cells compared
with those further apart from the tumor cells. FOXF1
expression in CAFs is not significantly associated with
any particular histologic subtypes of lung cancer and
also does not correlate with survival in the overall
population. However, lung cancer patients from the
female population or from the large cell lung cancer
population show positive correlation between FOXF1
expression in CAFs and predicted poor prognosis
(Saito et al., 2010). These IHC studies, in combination
with in vitro
functional studies of FOXF1 in fibroblasts (Saito et al.,
2010), suggest that FOXF1 plays an oncogenic role in
CAF-stimulated lung tumorigenesis.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7)
Alveolar capillary dysplasia with
misalignment of pulmonary veins
Disease
Alveolar capillary dysplasia with misalignment of
pulmonary veins (ACD/MPV) is a rare, neonatally
lethal developmental disorder of the lung with defining
histologic abnormalities typically associated with
multiple congenital anomalies (MCA). Infants with
ACD/MPV develop respiratory distress and severe
pulmonary hypertension within the first two days of
life. ACD/MPV-affected infants mostly can not survive
within the first month of life due to no sustained
response to supportive measures and respiratory failure.
More than 80% of infants with ACD/MPV have
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FOXF1 (forkhead box F1)
Lo PK
evolutionarily conserved DNA regions in forkhead box f1 gene
locus. J Biol Chem. 2005 Nov 11;280(45):37908-16
additional malformations occurring in the cardiac,
gastrointestinal, and genitourinary systems. Intestinal
malrotation is the most commonly observed of these
anomalies, and hypoplastic left heart together with
hypoplasia or coarctation of the aortic arch are the most
common associated cardiovascular abnormalities. Of
almost 200 reported ACD/MPV cases, approximately
10% have a familial association. Four distinct
heterozygous mutations (frameshift, nonsense, and nostop) were identified in the FOXF1 gene in unrelated
18 patients with sporadic ACD/MPV and MCA
(Stankiewicz et al., 2009), suggesting that an
impairment in the FOXF1 function might lead to these
observed developmental disorders.
Coon DR, Roberts DJ, Loscertales M, Kradin R. Differential
epithelial expression of SHH and FOXF1 in usual and
nonspecific interstitial pneumonia. Exp Mol Pathol. 2006
Apr;80(2):119-23
Ormestad M, Astorga J, Landgren H, Wang T, Johansson BR,
Miura N, Carlsson P. Foxf1 and Foxf2 control murine gut
development by limiting mesenchymal Wnt signaling and
promoting extracellular matrix production. Development. 2006
Mar;133(5):833-43
Astorga J, Carlsson P. Hedgehog induction of murine
vasculogenesis is mediated by Foxf1 and Bmp4. Development.
2007 Oct;134(20):3753-61
Wendling DS, Lück C, von Schweinitz D, Kappler R.
Characteristic overexpression of the forkhead box transcription
factor Foxf1 in Patched-associated tumors. Int J Mol Med.
2008 Dec;22(6):787-92
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This article should be referenced as such:
Lo PK. FOXF1 (forkhead box F1). Atlas Genet Cytogenet
Oncol Haematol. 2012; 16(7):467-470.
Kim IM, Zhou Y, Ramakrishna S, Hughes DE, Solway J, Costa
RH, Kalinichenko VV. Functional characterization of
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7)
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