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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review CITED4 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 4) Miguel Torres-Martin, Juan Antonio Rey Unidad de Investigacion del Hospital Universitario La Paz, Madrid, Spain (MTM, JAR) Published in Atlas Database: August 2009 Online updated version : http://AtlasGeneticsOncology.org/Genes/CITED4ID44535ch1p34.html DOI: 10.4267/2042/44794 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Description Identity CITED4 has a characteristic CITED domain motif conserved in all CITED peptides located at the carboxyl-terminal domain that binds with p300/CBP. Other names: MRG2; MRG-2 HGNC (Hugo): CITED4 Location: 1p34.2 Expression DNA/RNA In all tissues with special intensity in heart, liver, pancreas and skeletal muscle. Description Localisation DNA sequence is located at chromosome 1p. CITED4 has nuclear and cytoplasmatic location. In most cells it has a nuclear localization, but in others it was localized in nucleus and cytoplasm. Transcription Transcription consists of a single exon without alternative splicing. mRNA: NM_133467. 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. Protein Note CITED4 protein is 184 amino acid long with a molecular weight of 18569 Da. NP_597724. A. Position of CITED4 in the chromosome 1. B. Flanking genes of CITED4. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 633 CITED4 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 4) Torres-Martin M, Rey JA Coding and flanking regions of CITED4. 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 hypoxiainducible factor-1alpha transactivation and hypoxiamediated reporter gene activation. That is the reason why they concluded that CITED4 might be an inhibitor of hypoxia-inducible factor 1alpha. 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. 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). References Bragança J, Swingler T, Marques FI, Jones T, Eloranta JJ, Hurst HC, Shioda T, Bhattacharya S. Human CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) 4, a new member of the CITED family, functions as a coactivator for transcription factor AP-2. J Biol Chem. 2002 Mar 8;277(10):8559-65 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). Yahata T, Takedatsu H, Dunwoodie SL, Bragança J, Swingler T, Withington SL, Hur J, Coser KR, Isselbacher KJ, Bhattacharya S, Shioda T. Cloning of mouse Cited4, a member of the CITED family p300/CBP-binding transcriptional coactivators: induced expression in mammary epithelial cells. Genomics. 2002 Dec;80(6):601-13 Implicated in Oligodendroglioma Fox SB, Bragança J, Turley H, Campo L, Han C, Gatter KC, Bhattacharya S, Harris AL. 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. Cancer Res. 2004 Sep 1;64(17):6075-81 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. Tews B, Roerig P, Hartmann C, Hahn M, Felsberg J, Blaschke B, Sabel M, Kunitz A, Toedt G, Neben K, Benner A, von Deimling A, Reifenberger G, Lichter P. Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q. Oncogene. 2007 Jul 26;26(34):5010-6 Torres-Martín M, Franco-Hernandez C, Martinez-Glez V, de Campos JM, Isla A, Casartelli C, Rey JA. Mutational analysis of the CITED4 gene in glioblastomas. Cancer Genet Cytogenet. 2008 Sep;185(2):114-6 Breast cancer This article should be referenced as such: Note Cytoplasmatic translocation and loss of nuclear expression has been associated with breast cancer by Torres-Martin M, Rey JA. CITED4 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 4). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):633-634. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 634