CITED4 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 4)

2009-08-01 Miguel Torres-Martin , Juan Antonio Rey Affiliation

Unidad de Investigacion del Hospital Universitario La Paz, Madrid, Spain

Identity

HGNC

CITED4

LOCATION

1p34.2

IMAGE

LEGEND

A. Position of CITED4 in the chromosome 1. B. Flanking genes of CITED4.

LOCUSID

163732

ALIAS

FUSION GENES

Show Gene Fusions

DNA/RNA

Coding and flanking regions of CITED4.

Description

DNA sequence is located at chromosome 1p.

Transcription

Transcription consists of a single exon without alternative splicing. mRNA: NM_133467.

Proteins

Note

CITED4 protein is 184 amino acid long with a molecular weight of 18569 Da.
NP_597724.

Description

CITED4 has a characteristic CITED domain motif conserved in all CITED peptides located at the carboxyl-terminal domain that binds with p300/CBP.

Expression

In all tissues with special intensity in heart, liver, pancreas and skeletal muscle.

Localisation

CITED4 has nuclear and cytoplasmatic location. In most cells it has a nuclear localization, but in others it was localized in nucleus and cytoplasm.

Function

Binds CBP and tumor suppressor protein EP300 by carboxy terminus domain (residues 138-184). Therefore it may be implicated in gene transcription.
As other genes of the family, CITED4 physically interacts with transcription factor AP-2.
Fox et al. (2002) showed that CITED4 blocks the binding of hypoxia-inducible factor 1alpha to p300 in their experiments made in vitro and inhibits hypoxia-inducible factor-1alpha transactivation and hypoxia-mediated reporter gene activation. That is the reason why they concluded that CITED4 might be an inhibitor of hypoxia-inducible factor 1alpha.

Homology

CITED4 has 2 paralogues (CITED1 and CITED2) in humans. All of them belong to CITED family, found only in jawed vertebrates to date (Braganca et al., 2002).

Mutations

Note

No mutations has been reported yet, but a total of 16 polymorphisms with unknown consequences has been founded by Tews et al. (2007) and Torres-Martin et al. (2008).

Implicated in

Entity name

Oligodendroglioma

Note

CITED4 promoter is methylated in oligodendrogliomas, especially in those with 1p/19q deletions. This hypermethylation is responsible of lower levels of CITED4 mRNA expression, suggesting a way by which CITED4 is almost silenced by both hypermethylation and chromosomal deletion (Tews et al., 2007).

Prognosis

CITED4 hypermethylation in oligodendroglioma patients is similar to prognosis associated to 1p/19q deletions. Thus, CITED4 hypermethylation might be an alternative or even a confirmation of 1p/19q testing.

Entity name

Breast cancer

Note

Cytoplasmatic translocation and loss of nuclear expression has been associated with breast cancer by Fox et al. (2002). This loss may allow p300/CBP to interact with hypoxia-inducible factor 1a and oncogenes to enhance their transcriptional activity leading to an aggressive tumor phenotype (Fox et al., 2004).

Prognosis

CITED4 is located in the nucleus in normal tissue, but in breast tumors is present both nuclear and cytoplasmatic location. This characteristic might be used as prognosis factor of this kind of tumors.

Bibliography

Pubmed ID	Last Year	Title	Authors
11744733	2002	Human CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) 4, a new member of the CITED family, functions as a co-activator for transcription factor AP-2.	Bragança J et al
15342390	2004	CITED4 inhibits hypoxia-activated transcription in cancer cells, and its cytoplasmic location in breast cancer is associated with elevated expression of tumor cell hypoxia-inducible factor 1alpha.	Fox SB et al
17311001	2007	Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q.	Tews B et al
18722883	2008	Mutational analysis of the CITED4 gene in glioblastomas.	Torres-Martín M et al
12504852	2002	Cloning of mouse Cited4, a member of the CITED family p300/CBP-binding transcriptional coactivators: induced expression in mammary epithelial cells.	Yahata T et al

Other Information

Locus ID:

NCBI: 163732
MIM: 606815
HGNC: 18696
Ensembl: ENSG00000179862

Variants:

dbSNP: 163732
ClinVar: 163732
TCGA: ENSG00000179862
COSMIC: CITED4

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000179862	ENST00000372638	Q96RK1

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Gene Expression	REACTOME	R-HSA-74160
Generic Transcription Pathway	REACTOME	R-HSA-212436
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	REACTOME	R-HSA-8864260
Activation of the TFAP2 (AP-2) family of transcription factors	REACTOME	R-HSA-8866907

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
15572674	2004	Interaction and functional cooperation between the LIM protein FHL2, CBP/p300, and beta-catenin.	42
11744733	2002	Human CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) 4, a new member of the CITED family, functions as a co-activator for transcription factor AP-2.	38
20734064	2010	A large-scale candidate gene association study of age at menarche and age at natural menopause.	38
15342390	2004	CITED4 inhibits hypoxia-activated transcription in cancer cells, and its cytoplasmic location in breast cancer is associated with elevated expression of tumor cell hypoxia-inducible factor 1alpha.	24
17311001	2007	Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q.	15
21755341	2011	Aberrant DNA methylation but not mutation of CITED4 is associated with alteration of HIF-regulated genes in breast cancer.	7
26243458	2016	CITED4 gene silencing in colorectal cancer cells modulates adherens/tight junction gene expression and reduces cell proliferation.	6
18722883	2008	Mutational analysis of the CITED4 gene in glioblastomas.	1
29098625	2017	C/EBPB-CITED4 in Exercised Heart.	1

Citation

Miguel Torres-Martin ; Juan Antonio Rey

CITED4 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 4)

Atlas Genet Cytogenet Oncol Haematol. 2009-08-01

Online version: http://atlasgeneticsoncology.org/gene/44535/cited4-(cbp-p300-interacting-transactivator-with-glu-asp-rich-carboxy-terminal-domain-4)