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Gene Section
Review
TFAP2C (transcription factor AP-2 gamma
(activating enhancer binding protein 2 gamma))
Maria V Bogachek, Ronald J Weigel
Department of Surgery, Carver College of Medicine, University of Iowa, 5269 CBRB, 500 Newton
Road, Iowa City, Iowa 52242, USA (MVB), Department of Surgery, Carver College of Medicine,
University of Iowa, 200 Hawkins Drive Room 1509 JCP, Iowa City, Iowa 52242, USA (RJW)
Published in Atlas Database: October 2013
Online updated version : http://AtlasGeneticsOncology.org/Genes/TFAP2CID42528ch20q13.html
DOI: 10.4267/2042/53648
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
associated genes and repression
characteristic of the basal subtype.
Review on TFAP2C, with data on DNA/RNA, on
the protein encoded and where the gene is
implicated.
DNA/RNA
of
genes
Description
Identity
TFAP2C consists of 7 encoding exons. The open
reading frame of the coding region is 1353 bp.
TFAP2C cDNA was isolated in 1996 (Williamson
et al., 1996) and predicted protein was conserved
with TFAP2A DNA-binding and dimerization
domains, and differs in the N-terminal activation
domain.
The promoter lacks canonical binding sites for
basal transcription factors such as TATA and
CCAAT boxes, but contains a cluster of CpG
islands and may rely on an initiator element for
transcription (Li et al., 2002). A potential
trophoblast cell-specific regulatory element located
approximately 6 kb upstream of the murine Tfap2c
gene transcription start site (Li and Kellems, 2003).
Other names: AP2-GAMMA, ERF1, TFAP2G,
hAP-2g
HGNC (Hugo): TFAP2C
Location: 20q13.31
Note: TFAP2C is a member of the retinoic acidinducible, developmentally regulated family of AP2 factors. TFAP2C regulates cell growth and
differentiation during ectodermal development
(Qiao et al., 2012; Hoffman et al., 2007).
It plays a critical role in establishing the luminal
phenotype of normal mammary cells during their
differentiation process.
TFAP2C was shown to be involved in regulation of
ESR1 and luminal - associated genes in breast
cancer (Woodfield et al., 2010).
TFAP2C maintains breast cancer luminal
phenotype through the induction of luminal-
Transcription
3 splice variants are described (Ensembl).
Pseudogene
No pseudogenes are reported.
TFAP2C human gene including promoter, 7 exons (blue rectangles) and 6 introns. Modified from Entrez Gene (Genomic DNA).
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5)
346
TFAP2C (transcription factor AP-2
enhancer binding protein 2 gamma))
gamma
(activating
Bogachek MV, Weigel RJ
Assignment of TFAP2C functional domains. AA: aminoacids, K10: SUMOylation site, AD: activation domain, Di/DBD:
dimerization domain/DNA binding domain (adapted from Williams and Tjian, 1991).
TFAP2C silencing coincided with acquisition of an
active chromatin conformation at the CDKN1A
locus and increased gene expression (Gee et al.,
2009).
TFAP2C SUMOylation modification was described
in mammalian cells and SUMO site was mapped to
conserved lysine 10 (Eloranta and Hurst, 2002).
Epithelial hyperplasia and impaired differentiation
were reported in Tfap2c overexpressing transgenic
mice (Jäger et al., 2003).
Protein
Note
Active TFAP2C forms consist of homo - and
heterodimers and play an important role in
activation of retinoic acid-mediated differentiation
including development of the eyes, face, body wall,
limbs, neural tube (Hoffman et al., 2007; Li and
Cornell, 2007).
Placental defect and embryonic death were reported
as results of TFAP2C total knockdown.
TFAP2C protein was purified in 1997 (McPherson
et al., 1997) from ESR1 - positive cell line, was
designed as ERF1. TFAP2C, 450-aa protein, has 48
kDa molecular mass.
TFAP2C has 65% sequence homology to TFAP2A
overall and 76% identity in C-terminal part.
The consensus site from the ChIP-seq data,
SCCTSRGGS (S=G/C, r=A/G), is consistent with
the optimal binding site, GCCTGAGGG, which
was determined by in vitro PCR-assisted binding
site selection (Woodfield et al., 2010).
Estrogen receptor-alpha (ESR1) and HER2/c-erbB2
genes are regulated by TFAP2C (Bosher et al.,
1995; McPherson et al., 1997; Delacroix et al.,
2005; Woodfield et al., 2007) along with genes
associated with luminal phenotype of breast cancer
(Woodfield et al., 2010).
Activity of TFAP2C at specific target genes
depends upon epigenetic chromatin structure.
The combination of increasing chromatin
accessibility and inducing TFAP2C provides a
more robust activation of the ESR1 gene in ESR1negative breast cancer cells (Woodfield et al.,
2009).
TFAP2C repressed CD44 expression in basalderived breast cancer (Spanheimer et al., 2013a).
TFAP2C regulates the expression of GPX1, which
influences the redox state and sensitivity to
oxidative stress induced by peroxides (Kulak et al.,
2013).
Wwox tumor suppressor protein inhibits TFAP2C
oncogenic activity by sequestering it in the
cytoplasm (Aqeilan et al., 2004).
Reporter and chromatin immunoprecipitation
assays demonstrated a direct, functional interaction
by TFAP2C at the CDKN1A proximal promoter.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5)
Description
A helixloop-helix motif in the DNA binding
domain binds to GC-rich consensus site,
SCCTSRGGS (S=G/C, R=A/G) (Woodfield et al.,
2010), in the promoters of target genes and
mediates TFAP2C specific transcriptional activity.
Expression
TFAP2C is widely expressed within secondary
outgrowths in the human mammary gland by 19
weeks gestation.
In the adult mammary gland TFAP2C expression
can be found in epithelial and myoepithelial
compartments.
TFAP2C expression was reported in 16-40 weeks
placenta, 5-10 weeks decidu and chorion (Li et al.,
2002).
TFAP2C is expressed in gonocytes at weeks 12-37
of gestation, indicating a role of this transcription
factor in fetal germ cell development.
TFAP2C and c-KIT, a known target of AP-2
transcription factors, were coexpressed in
gonocytes, making a direct regulation possible.
With increasing differentiation of fetal testis,
gradual downregulation of TFAP2C from the 12th
to 37th week of gestation was observed.
Furthermore, TFAP2C was expressed abundantly in
25/25 IGCNUs, 52/53 testicular seminomas, 10/10
metastatic seminomas, 9/9 extragonadal seminomas
and 5/5 dysgerminomas (Pauls et al., 2005).
Normal tissues with TFAP2C expression: colon,
lymph node, brain, heart, kidney, liver, lung,
thyroid, adrenal gland, ovary, prostate, testis.
Localisation
Nuclear.
347
TFAP2C (transcription factor AP-2
enhancer binding protein 2 gamma))
gamma
(activating
Bogachek MV, Weigel RJ
Function
TFAP2C gene expression (Li and Kellems, 2003).
It plays a role in the development of the eyes, face,
body wall, limbs, and neural tube (Hoffman et al.,
2007; Li and Cornell, 2007).
Deletion of Tcfap2c during development resulted in
a specific reduction of upper layer neurons in the
occipital cortex (Pinto et al., 2009).
Conditional ablation of Tcfap2c results in a delay in
skin development and abnormal expression of p63,
K14, K1, filaggrin, repetin and secreted Ly6/Plaur
domain containing 1, key genes required for
epidermal
development
and
differentiation
(Guttormsen et al., 2008). Heterozygous Tfap2cknockout mice were detected to have decreased
body size while homozygous mice died at 7-9 days
of embryonic development due to failure of
proliferation of extraembryonic trophectodermal
cells (Werling and Schorle, 2002). TFAP2C is also
implicated in the regulation of the adenosine
deaminase (ADA) gene, a gene involved in purine
metabolism found expressed at the maternal-fetal
interface (Werling and Schorle, 2002).
Implicated in
Breast cancer
Note
TFAP2C plays a critical role in maintaining the
luminal subtype of breast cancer. TFAP2C directly
binds to promoters and activates ESR1 along with
luminal-associated genes (Woodfield et al., 2010).
TFAP2C repressed CD44 expression in basalderived breast cancer (Spanheimer et al., 2013a).
Regulation of Ret by TFAP2C occurs
independently of ESR1 expression in breast
carcinoma (Spanheimer et al., 2013b). TFAP2C
regulates the expression of GPX1, which influences
the redox state and sensitivity to oxidative stress
induced by peroxides (Kulak et al., 2013).
Prognosis
Resistance to Tamoxifen treatment and reduction of
survival rate had correlation with TFAP2C
overexpression (Guler et al., 2007). ERBB2negative/AP-2-positive expression patients had a
better prognosis than patients with ERBB2positive/AP-2-positive tumors (Gee et al., 2009).
In primary breast cancer specimens, high TFAP2C
and low CD44 expression were associated with
pCR after neoadjuvant chemotherapy and could be
predictive of tumors that have improved response to
neoadjuvant chemotherapy (Spanheimer et al.,
2013a).
Elevated expression levels of TFAP2C in breast
tumors were reported as predictors of poor
prognosis (Zhao et al., 2003) and advancing clinical
grade (Sotiriou et al., 2006).
Homology
Mouse, Tfap2c (Mus musculus: NP_033361.2)
(NCBI).
Predicted homology: chicken (Gallus gallus:
XM_417497.4),
zebrafish
(Danio
rerio:
NM_001008576.1) (NCBI).
Mutations
Germinal
2 patients with deletions of chromosome 20q13.2q13.3 were reported to have feeding difficulties,
microcephaly, facial dysmorphism with high
forehead, broad nasal bridge, small chin and
malformed ears, mild psychomotor retardation, and
hypotonia (Geneviève et al., 2005).
Seminomatous germ cell tumors
Note
Immunohistochemistry marker to the detection of
germ cell tumors (Pauls et al., 2005).
Somatic
Melanoma
39 mutations were detected after analysis of 8164
samples (COSMIC: gene overview for TFAP2C)
without direct links to certain diseases
pathogenesis.
Deletion analyses of the promoter and
chloramphenicol acetyl transferase reporter gene
assays indicate that the sequence between -746 and
-575 is important for its expression in mammary
carcinoma cell lines (Li et al., 2002).
Combined mutation of the three putative Sp sites
reduced promoter activity by 80% in trophoblast
and nontrophoblast cells, demonstrating the
functional importance of these sites in regulating
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5)
Note
AP-2γ expression is lower in thick melanomas, it is
associated with unfavourable histo-pathological
parameters (increased vascularity, vascular invasion
and mitoses) (Osella-Abate et al., 2012).
Pre-eclampsia
Note
Elevated TFAP2C concentrations are associated
with human placental defects such as pre-eclampsia
and intrauterine growth restriction (Kuckenberg et
al., 2012).
348
TFAP2C (transcription factor AP-2
enhancer binding protein 2 gamma))
gamma
(activating
Bogachek MV, Weigel RJ
TFAP2C target genes. Analysis was done by Ingenuity Systems. Red tone indicates genes repressed by TFAP2C and green
indicates genes induced by TFAP2C. Insert: TFAP2C target genes RXR, RAR, and CRABP2 are involved in the retinoic acid
signaling pathway (Woodfield et al., 2010).
Acad Sci U S A. 1995 Jan 31;92(3):744-7
Breakpoints
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