CITED2 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2)

2010-01-01   Matthias Haase , Holger S Willenberg 

Department of Endocrinology, Diabetes, Rheumatology, University Hospital Duesseldorf, 40225 Duesseldorf, Germany





The CITED2-Gene is composed of three exons and two introns. The gene encompasses 9,39 kb of DNA. The promoter contains hypoxia response elements, SP1 binding sites, STAT binding sites and a NFkappaB binding site (Leung et al., 1999).


By splicing processes two different transcripts are generated: in the p35srj-transcript there is only one intron spliced out and it still contains the intron 2 coding for a serine rich junction (srj). In the MRG1-transcript both introns are spliced out (Leung et al., 1999).



Isoform p35srj: 270 aa, 28,5 kDa (molecular weight calculated by amino acid sequence).
Isoform MRG1: 213 aa, 23,73 kDa (molecular weight calculated by amino acid sequence).


Widely expressed, developmental regulated.


Predominantly nuclear.


Transcriptional co-regulator. The CITED2 isoform p35srj binds to p300/CBP and inhibits HIF-1alpha transactivation (Bhattacharya et al., 1999). CITED2 competes with HIF-1alpha for an overlapping binding site on the cysteine-histidine-rich 1 domain of p300 (Freedman et al., 2003). CITED2 was identified as a co-activator of all isoforms of the transcription factor AP-2 (TFAP2, Bamforth et al., 2001; Braganca et al., 2003). Overexpression of MRG1 resulted in tumor formation in nude mice (Sun et al., 1998). CITED2 controls fibroblast proliferation by the regulation of the proliferation inhibitors INK4a/ARF and the polycomb-group genes BMI1/Mel18 (Kranc et al., 2003). CITED2 is a co-regulator of the peroxisome proliferator-activated receptor alpha (PPARalpha) and increases proliferation in hepatocytes (Tien et al., 2004). CITED2 regulates the Nodal-Pitx2c pathway and controls developmental processes (Bamforth et al., 2004). CITED2 is a co-activator of Smad3/p300 transcription and modulates metalloproteinase 9 expression in a transforming growth factor beta (TGF-beta) dependent pathway (Chou et al., 2006).



Amino acid changing mutations (p.Ser170_Gly178del, p.Gly178_Ser179ins9 and p.Ser198_Gly199del) in the serine-glycine-rich junction of the protein. The mutants show decreased transrepression of HIF-1a or decreased coactivation of TFAP2. The mutations mentioned above have been detected in patients suffering from congenital heart defects (cardiac septal defects) but not in normal individuals (Sperling et al., 2005).

Implicated in

Entity name
Adrenocortical carcinoma
CITED2 is expressed in adrenocortical carcinomas as well as in the adrenocortical carcinoma cell line NCI-H295R. CITED2 is upregulated by bFGF, Forskolin, endothelial cell products and Angiotensin II in NCI-H295R cells (Haase et al., 2007; Romero et al., 2007; Haase et al., 2009). In part, CITED2-expression in adrenocortical carcinomas could be observed in close proximity to blood vessels (Haase et al., 2009).
Entity name
Breast cancer
CITED2 is highly expressed in MDA-MB-231 invasive breast cancer cells which are resistant to TGF-beta mediated growth arrest. TGF-beta induced MDA-MB-231 cell invasion could be reduced by downregulation of CITED2 as an enhancer of metalloproteinase 9 (MMP9)-expression, suggesting a role for CITED2 during tumor invasion (Chou et al., 2005). In Fibroblasts and in breast cancer cells FOXO3a inhibits HIF-1 induced apoptosis via upregulation of CITED2 (Bakker et al., 2007). CITED2 was especially expressed in human breast cancer cell lines that form osteolytic metastases in animal models. Elevated expression of CITED2 could also be observed in invasive ductal carcinoma tissue samples and in breast cancer bone metastases in comparison to normal mammary epithelial tissues (Lau et al., 2010). A study from Agthoven et al., observed that high levels of CITED2 mRNA in oestrogen receptor-alpha positive breast tumors of lymph-node negative patients were associated with prolonged metastasis-free-survival. In the same study high levels of CITED2 mRNA were also associated with a favourable outcome in patients that have received Tamoxifen as a first line therapy (van Agthoven et al., 2009).
Entity name
Colorectal cancer
In a human colorectal carcinoma cell line CITED2 is downregulated by Rac1, a protein that has been associated with tumor growth (Gomez del Pulgar et al., 2007). In the human colon cancer cell line RKO downregulation of CITED2 increased colon cancer cell invasivness and upregulated MMP-13 expression (Bai et al., 2007).
Entity name
Esophageal cancer
CITED2 was downregulated in a well and a poorly differentiated esophageal cancer cell line after treatment with up to 8 Gy irradiation (Bo et al., 2004).
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GnRHa therapy increased CITED2 expression in leiomyoma and myometrium. GnRHa therapy had a biphasic effect on CITED2 expression in primary cultures of myometrial smooth muscle cells and inhibits expression in primary cultures of leiomyoma smooth muscle cells (Luo et al., 2005b). Expression of CITED2 was downregulated by TGF-beta in primary cultures of myometrial and leiomyoma smooth muscle cells (Luo et al., 2005a).
Entity name
CITED2 is downregulated in radiation-induced rat osteosarcoma as compared with normal osteoblasts (Daino et al., 2009). The analysis of radiation-induced rat osteosarcoma showed reduced mRNA and protein expression and suggests a role for CITED2 as a tumor supressor gene in osteosarcoma (Daino et al., 2009).
Entity name
Ovarian carcinoma
CITED2 expression was significantly downregulated after silencing of the tumor susceptibility gene 101 protein (TSG101) in SKOV-3 ovarian cancer cells with elevated RAS activity. The downregulation of CITED2 went along with a decrease of cell viability (Young et al., 2007). Expression of CITED2 was elevated in the oxaliplatin resistant cell line KFR as compared with the oxaliplatin sensitive cell line KF-1. The downregulation of CITED2 in the platinum-resistent ovarian cancer cell line KFR enhances the cytotoxicity of platinum compounds to the KFR cell line (Yanangie et al., 2009).
Entity name
Ewings-Sarcoma show a 6-fold increase in CITED2-expression as compared with rhabdomyosarcoma (Baer et al., 2004).
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Adrenal development and adrenocortical physiology
CITED2-null mice show adrenal agenesis indicating a role for CITED2 within adrenal development (Bamforth et al., 2001). At 8 weeks of gestation CITED2 could be detected especially within the definitive zone of the developing adrenal cortex (Haase et al., 2007). Following studies confirmed the expression of CITED2 during early human fetal adrenal gland development at 7 and 10 weeks of gestation (Ferraz-de-Souza et al., 2009). In mice CITED2 was expressed in the coelomic epithelium and in the nephrogenic mesenchyme at E10. At E12 CITED2 was highly expressed in the adrenal primordium and remained highly expressed in adrenocortical cells at E13.5 and later (Val et al., 2007). In mice CITED2 acts as a WT-1 co-factor to increase SF-1 levels in the adrenogonadal primordium to initiate adrenal development (Val et al., 2007). Other studies applying human NCI-H295R adrenal carcinoma cells demonstrate that SF-1 activates the CITED2-promoter (Ferraz-de-Souza et al., 2009). In human NCI-H295R cells CITED2-expression is regulated by basic fibroblast growth factor, endothelial cell products and is dependent on the MAPK-pathway (Haase et al., 2007; Haase et al., 2009). Forskolin could also be identified as a positive regulator of CITED2-expression in NCI-H295R cells (Haase et al., 2007; Romero et al., 2007). Angiotensin II upregulates CITED2-expression in NCI-H295R cells and CITED2 enhances the expression of steroidogenic enzymes such as 11-beta-Hydroxylase and Aldosterone-Synthase (Romero et al., 2007).
Entity name
Congenital heart defects and cardiac septal defects
CITED2 -/- mice show cardiac malformations including ventricular and atrial septal defects, double-outlet right ventricle, overriding aorta, right sided aortic arches and persistent truncus arteriosus (Bamforth et al., 2001). Functional loss of CITED2 during transrepression of HIF-1 alpha has been suggested to be responsible for the observed phenotype (Yin et al., 2002). Aberrant signaling of the Nodal-Pitx2c pathway has also been linked to the cardiovascular defects observed in CITED2 -/- mice (Bamforth et al., 2004). Aberrant left-right patterning as well as direct loss of CITED2 in cardiac tissues has been associated with the defects in CITED2-null mice (Weninger et al., 2005). The cardiovascular defects seem to result from the disruption of left-right patterning in epiblast derivatives and from the malfunction of septation in the mesoderm (MacDonald et al., 2008).
Mutations of CITED2 in humans have been linked to cardiac septal defects and congenital heart defects (Sperling et al., 2005).
Entity name
Exencephaly, neural crest defects and neurologic implications
CITED2-null mice show exencephaly, abnormal cranial ganglia, neural crest defects and increased apoptosis in the midbrain region (Bamforth et al., 2001). Exencephaly seem to arise from defective closure of the midbrain and hindbrain region, associated with a defective closure of the neural tube (Barbera et al., 2002). Apoptosis around the Forebrain-Midbrain-junction in the dorsal neuroectoderm was increased in CITED2 -/- mice and CITED2 was necessary for the survival of neuroepithelial cells (Barbera et al., 2002). The administration of folic acid significantly reduced exencephaly in CITED2-null mice (Barbera et al., 2002). Transient forebrain ischemia induced CITED2-expression in different brain regions including the piriform cortex and the dentate gyrus of the hippocampal region and it has been speculated if CITED2 protects from neuronal death under hypoxic conditions (Sun et al., 2006). However, other studies also demonstrate that CITED2-overexpression can promote cell death in cortical neurons of the mouse (Gonzales et al., 2008). CITED2 expression is increased after olfactory bulbectomy and may contribute to the phenotype of basal progenitor cells of the olfactory sensory neuron lineage in the mouse (Shetty et al., 2005). CITED2 was also identified as a neural activity-dependent transcription-factor in vivo and in vitro in rat cortical neurons (Sun et al., 2007).
Entity name
Eye developement
CITED2 is necessary for the morphogenesis of the lens and for hyaloid vasculature formation (Chen et al., 2008). Selective deletion of CITED2 resulted in abnormal corneal epithelial differentiation, impaired wound healing and corneal neovascularization in older mice associated with decreased expression of Pax6 and Klf4 (Chen et al., 2009).
Entity name
Fracture healing
CITED2 was identified as a negative regulator of fracture healing in rats and was inversly related to the expression of metalloproteinases (MMP-2, MMP-3, MMP-9, MMP-13), HIF-1a, VEGF, RANK-L, M-CSF and OPG (Lee et al., 2009).
Entity name
Gonadal development
In CITED2 null mice XY-gonad development was delayed and testis structure was disorganized. In XX-gonads of CITED2 null mice cell migration was disturbed (Combes et al., 2009). CITED2 interacts with Wt1 and SF-1 in mice and increases Sry levels initiating testes development (Buaas et al., 2009).
Entity name
CITED2 is required for the regulation of hematopoeisis during embryogenesis in the murine fetal liver (Chen et al., 2007). CITED2 controls adult hematopoietic stem cell function via Ink4a/Arf and Trp53 (Kranc et al., 2009).
Entity name
Liver development
CITED2 null mice show liver hypoplasia, increased apoptosis, disrupted sinusoidal architecture, disrupted cell-cell contacts, impaired lipid metabolism and gluconeogenesis. The observations have been linked to the role of CITED2 as a co-activator of HNF4alpha (Qu et al., 2007).
Entity name
Lung development
CITED2 is required for fetal lung maturation. Terminal sac space and differentiation of alveolar epithelial cells Typ 1 and 2 is altered in CITED2 null lungs in mice (Xu et al., 2008). CITED2 is developmentally regulated in pulmonary artery smooth muscle cells in sheep with higher expression in the fetus compared with the adult (Resnik et al., 2007).


Pubmed IDLast YearTitleAuthors
151465582004Profiling and functional annotation of mRNA gene expression in pediatric rhabdomyosarcoma and Ewing's sarcoma.Baer C et al
180543362007A role for CITED2, a CBP/p300 interacting protein, in colon cancer cell invasion.Bai L et al
181588932007FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2.Bakker WJ et al
154759562004Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway.Bamforth SD et al
118234472002Folic acid prevents exencephaly in Cited2 deficient mice.Barbera JP et al
98871001999Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1.Bhattacharya S et al
152266082004Effect of ionizing irradiation on human esophageal cancer cell lines by cDNA microarray gene expression analysis.Bo H et al
125868402003Physical and functional interactions among AP-2 transcription factors, p300/CREB-binding protein, and CITED2.Bragança J et al
194579262009The transcription co-factor CITED2 functions during sex determination and early gonad development.Buaas FW et al
196322192009Conditional deletion of Cited2 results in defective corneal epithelial morphogenesis and maintenance.Chen Y et al
186535622008Cited2 is required for the proper formation of the hyaloid vasculature and for lens morphogenesis.Chen Y et al
176447322007Cited2 is required for normal hematopoiesis in the murine fetal liver.Chen Y et al
166190372006Cited2 modulates TGF-beta-mediated upregulation of MMP9.Chou YT et al
197573802010Gonadal defects in Cited2-mutant mice indicate a role for SF1 in both testis and ovary differentiation.Combes AN et al
194449102009Gene expression profiling of alpha-radiation-induced rat osteosarcomas: identification of dysregulated genes involved in radiation-induced tumorigenesis of bone.Daino K et al
189846682009CBP/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 2, and pre-B-cell leukemia transcription factor 1 in human adrenal development and disease.Ferraz-de-Souza B et al
127781142003Structural basis for negative regulation of hypoxia-inducible factor-1alpha by CITED2.Freedman SJ et al
177661702007Differential expression of Rac1 identifies its target genes and its contribution to progression of colorectal cancer.Gómez del Pulgar T et al
184958902008CITED2 signals through peroxisome proliferator-activated receptor-gamma to regulate death of cortical neurons after DNA damage.Gonzalez YR et al
193195722009Evidence for the involvement of endothelial cell products in adrenal CITED2 expression.Haase M et al
172832462007CITED2 is expressed in human adrenocortical cells and regulated by basic fibroblast growth factor.Haase M et al
145600112003Transcriptional coactivator Cited2 induces Bmi1 and Mel18 and controls fibroblast proliferation via Ink4a/ARF.Kranc KR et al
199516932009Cited2 is an essential regulator of adult hematopoietic stem cells.Kranc KR et al
196421062010Identification of prospective factors promoting osteotropism in breast cancer: a potential role for CITED2.Lau WM et al
196078042009Identification of CITED2 as a negative regulator of fracture healing.Lee JY et al
105529321999Molecular cloning and chromosomal localization of the human CITED2 gene encoding p35srj/Mrg1.Leung MK et al
156042082005Leiomyoma and myometrial gene expression profiles and their responses to gonadotropin-releasing hormone analog therapy.Luo X et al
184409892008Epiblastic Cited2 deficiency results in cardiac phenotypic heterogeneity and provides a mechanism for haploinsufficiency.MacDonald ST et al
179324832007Cited2, a coactivator of HNF4alpha, is essential for liver development.Qu X et al
180000552007Developmental regulation of hypoxia-inducible factor 1 and prolyl-hydroxylases in pulmonary vascular smooth muscle cells.Resnik ER et al
173274932007Adrenal transcription regulatory genes modulated by angiotensin II and their role in steroidogenesis.Romero DG et al
164569262005Transcriptional changes during neuronal death and replacement in the olfactory epithelium.Shetty RS et al
89015751996msg1, a novel melanocyte-specific gene, encodes a nuclear protein and is associated with pigmentation.Shioda T et al
162871392005Identification and functional analysis of CITED2 mutations in patients with congenital heart defects.Sperling S et al
98118381998MRG1, the product of a melanocyte-specific gene related gene, is a cytokine-inducible transcription factor with transformation activity.Sun HB et al
171162342007Identification and characterization of novel activity-dependent transcription factors in rat cortical neurons.Sun W et al
164340292006Induction of CITED2 expression in the rat hippocampus following transient global ischemia.Sun W et al
150517272004Identification of the CREB-binding protein/p300-interacting protein CITED2 as a peroxisome proliferator-activated receptor alpha coregulator.Tien ES et al
175377992007Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage.Val P et al
157501852005Cited2 is required both for heart morphogenesis and establishment of the left-right axis in mouse development.Weninger WJ et al
183584662008Cited2 is required for fetal lung maturation.Xu B et al
185718922009Improvement of sensitivity to platinum compound with siRNA knockdown of upregulated genes in platinum complex-resistant ovarian cancer cells in vitro.Yanagie H et al
121494782002The essential role of Cited2, a negative regulator for HIF-1alpha, in heart development and neurulation.Yin Z et al
171104342007Up-regulation of tumor susceptibility gene 101 protein in ovarian carcinomas revealed by proteomics analyses.Young TW et al
199042692009CITED2 and NCOR2 in anti-oestrogen resistance and progression of breast cancer.van Agthoven T et al

Other Information

Locus ID:

NCBI: 10370
MIM: 602937
HGNC: 1987
Ensembl: ENSG00000164442


dbSNP: 10370
ClinVar: 10370
TCGA: ENSG00000164442


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Cellular responses to stressREACTOMER-HSA-2262752
Cellular response to hypoxiaREACTOMER-HSA-2262749
Regulation of Hypoxia-inducible Factor (HIF) by oxygenREACTOMER-HSA-1234174
Regulation of gene expression by Hypoxia-inducible FactorREACTOMER-HSA-1234158
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factorsREACTOMER-HSA-8864260
Activation of the TFAP2 (AP-2) family of transcription factorsREACTOMER-HSA-8866907
TFAP2 (AP-2) family regulates transcription of other transcription factorsREACTOMER-HSA-8866906
Mitophagy - animalKEGGko04137
Mitophagy - animalKEGGhsa04137

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
268512782016Role of Intrinsic Protein Disorder in the Function and Interactions of the Transcriptional Coactivators CREB-binding Protein (CBP) and p300.51
129601752003CITED2-mediated regulation of MMP-1 and MMP-13 in human chondrocytes under flow shear.41
150517272004Identification of the CREB-binding protein/p300-interacting protein CITED2 as a peroxisome proliferator-activated receptor alpha coregulator.40
282730702017Hypersensitive termination of the hypoxic response by a disordered protein switch.37
162871392005Identification and functional analysis of CITED2 mutations in patients with congenital heart defects.35
162871392005Identification and functional analysis of CITED2 mutations in patients with congenital heart defects.35
179324832007Cited2, a coactivator of HNF4alpha, is essential for liver development.31
180543362007A role for CITED2, a CBP/p300 interacting protein, in colon cancer cell invasion.23
210982202011Negative feedback regulation of NF-κB action by CITED2 in the nucleus.20
199042692009CITED2 and NCOR2 in anti-oestrogen resistance and progression of breast cancer.19


Matthias Haase ; Holger S Willenberg

CITED2 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2)

Atlas Genet Cytogenet Oncol Haematol. 2010-01-01

Online version: