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Gene Review

CITED2  -  Cbp/p300-interacting transactivator, with...

Homo sapiens

Synonyms: ASD8, Cbp/p300-interacting transactivator 2, MRG-1, MRG1, MSG-related protein 1, ...
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Disease relevance of CITED2

  • The transcription factor CITED2 binds p300/CBP at the CH1 domain and functions as a negative regulator of hypoxia signaling by competing with hypoxia-inducible factor 1alpha [1].
  • We present for the first time functionally relevant mutations of CITED2 in patients with congenital heart defects (CHDs) [2].
  • Induction of CITED2 expression in the rat hippocampus following transient global ischemia [3].
  • In this study, we confirmed that both mRNA and protein levels of Cited2 are down-regulated in MDA-MB-231 breast cancer cells [4].

High impact information on CITED2

  • The high-resolution solution structure of the CITED2 TAD-p300 CH1 complex shows that the CITED2 TAD, like the HIF-1alpha C-TAD, folds on a helical, Zn2+-containing CH1 scaffold [5].
  • These findings reveal that CITED2 regulates HIF-1 by competing for a hot spot on the p300 CH1 domain [5].
  • This is the first demonstration that TGF-beta-mediated down-regulation of Cited2 is post-transcriptional, through the Smad pathway, and requires the presence of its coding sequence [4].
  • We examined the expression of recombinant Cited2 gene introduced into MDA-MB-231 cells by stable transfection, and we found that mRNA containing the Cited2 protein-coding region controlled by a heterologous promoter indeed responds to TGF-beta-mediated down-regulation [4].
  • Through microarray analysis, Cited2 was found to be down-regulated by transforming growth factor beta1 (TGF-beta) in various cell lines [4].

Chemical compound and disease context of CITED2


Biological context of CITED2


Anatomical context of CITED2

  • Using the immortalized human chondrocyte cell line, C-28/I2, we investigated whether CITED2 could be responsive to mechanical stimuli, and if so, whether CITED2 could mediate shear-driven regulation of matrix metalloproteinase (MMP) genes [6].
  • Gene knockout studies indicate that CITED2 is required for neural crest and neural tube development and that it functions as a co-activator for transcription factor AP-2 (TFAP2) [9].
  • These studies identify a hierarchical network of transcription factors, including Wilms' tumor-1, steroidogenic factor-1, dosage-sensitive sex reversal, adrenal hypoplasia congenita, X-linked-1, PBX1, and CITED2, that both give rise to the adrenal cortex and subsequently determine its subsequent function in steroidogenesis [10].
  • The persistent hypoxia and abnormal vasculature in the myocardium of interventricular septum in E15.5 Cited2(-/-) hearts were rescued with decreased HIF-1alpha gene dosage [11].
  • Moreover, immunoblot analysis using mutant animals with germline deficiencies indicated that MRG-1 is synthesized predominantly in oocytes [12].

Associations of CITED2 with chemical compounds

  • Pharmacologic inhibition of translation with cycloheximide attenuated Cited2 down-regulation by TGF-beta [4].
  • This may occur through a direct physical association of Cited2 with Smads 2 and 3, as supported by co-immunoprecipitation, mammalian two-hybrid and glutathione S-transferase-pull down assays [13].
  • There were gene specific differences, the PS2 and TGFbeta3 genes were about equally sensitive to Zeranol, 17beta-oestradiol and DES whereas a down-regulation of MRG1/p35srj could be detected at fmol/l concentrations of Zeranol whereas 17beta-oestradiol was several orders of magnitude less potent [14].

Physical interactions of CITED2

  • In mammalian two-hybrid experiments, full-length p300 and TFAP2A interacted only when CITED2 was co-transfected [15].

Regulatory relationships of CITED2

  • The results showed that flow shear at 5 dyn/cm2 increased CITED2 mRNA and protein levels and down-regulated MMP-1 and MMP-13 mRNA and protein levels as well as enzyme activities [6].
  • These data suggest a model in which the Lhx2 LIM domain activates transcription through interaction with MRG1 leading to recruitment of p300/CBP and the TATA-binding protein [16].

Other interactions of CITED2

  • The CITED2 TAD binds a different, more extensive surface of CH1 than does the HIF-1alpha C-TAD [5].
  • CITED2 is implicated in the modulating the activity of HIF-1 which is a major transcription factor involved in ischemia-related gene expression [3].

Analytical, diagnostic and therapeutic context of CITED2


  1. 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, S.B., Bragança, J., Turley, H., Campo, L., Han, C., Gatter, K.C., Bhattacharya, S., Harris, A.L. Cancer Res. (2004) [Pubmed]
  2. Identification and functional analysis of CITED2 mutations in patients with congenital heart defects. Sperling, S., Grimm, C.H., Dunkel, I., Mebus, S., Sperling, H.P., Ebner, A., Galli, R., Lehrach, H., Fusch, C., Berger, F., Hammer, S. Hum. Mutat. (2005) [Pubmed]
  3. Induction of CITED2 expression in the rat hippocampus following transient global ischemia. Sun, W., Kim, K.H., Noh, M., Hong, S., Huh, P.W., Kim, Y., Kim, H. Brain Res. (2006) [Pubmed]
  4. Post-transcriptional control of Cited2 by transforming growth factor beta. Regulation via Smads and Cited2 coding region. Chou, Y.T., Yang, Y.C. J. Biol. Chem. (2006) [Pubmed]
  5. Structural basis for negative regulation of hypoxia-inducible factor-1alpha by CITED2. Freedman, S.J., Sun, Z.Y., Kung, A.L., France, D.S., Wagner, G., Eck, M.J. Nat. Struct. Biol. (2003) [Pubmed]
  6. CITED2-mediated regulation of MMP-1 and MMP-13 in human chondrocytes under flow shear. Yokota, H., Goldring, M.B., Sun, H.B. J. Biol. Chem. (2003) [Pubmed]
  7. Identification of the CREB-binding protein/p300-interacting protein CITED2 as a peroxisome proliferator-activated receptor alpha coregulator. Tien, E.S., Davis, J.W., Vanden Heuvel, J.P. J. Biol. Chem. (2004) [Pubmed]
  8. Molecular cloning and chromosomal localization of the human CITED2 gene encoding p35srj/Mrg1. Leung, M.K., Jones, T., Michels, C.L., Livingston, D.M., Bhattacharya, S. Genomics (1999) [Pubmed]
  9. 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., Swingler, T., Marques, F.I., Jones, T., Eloranta, J.J., Hurst, H.C., Shioda, T., Bhattacharya, S. J. Biol. Chem. (2002) [Pubmed]
  10. Minireview: transcriptional regulation of adrenocortical development. Hammer, G.D., Parker, K.L., Schimmer, B.P. Endocrinology (2005) [Pubmed]
  11. Partial rescue of defects in Cited2-deficient embryos by HIF-1alpha heterozygosity. Xu, B., Doughman, Y., Turakhia, M., Jiang, W., Landsettle, C.E., Agani, F.H., Semenza, G.L., Watanabe, M., Yang, Y.C. Dev. Biol. (2007) [Pubmed]
  12. MRG-1, a mortality factor-related chromodomain protein, is required maternally for primordial germ cells to initiate mitotic proliferation in C. elegans. Fujita, M., Takasaki, T., Nakajima, N., Kawano, T., Shimura, Y., Sakamoto, H. Mech. Dev. (2002) [Pubmed]
  13. Cited2 modulates TGF-beta-mediated upregulation of MMP9. Chou, Y.T., Wang, H., Chen, Y., Danielpour, D., Yang, Y.C. Oncogene (2006) [Pubmed]
  14. Oestrogenic potencies of Zeranol, oestradiol, diethylstilboestrol, Bisphenol-A and genistein: implications for exposure assessment of potential endocrine disrupters. Leffers, H., Naesby, M., Vendelbo, B., Skakkebaek, N.E., Jørgensen, M. Hum. Reprod. (2001) [Pubmed]
  15. Physical and functional interactions among AP-2 transcription factors, p300/CREB-binding protein, and CITED2. Bragança, J., Eloranta, J.J., Bamforth, S.D., Ibbitt, J.C., Hurst, H.C., Bhattacharya, S. J. Biol. Chem. (2003) [Pubmed]
  16. MRG1 binds to the LIM domain of Lhx2 and may function as a coactivator to stimulate glycoprotein hormone alpha-subunit gene expression. Glenn, D.J., Maurer, R.A. J. Biol. Chem. (1999) [Pubmed]
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