Abstract

Members of the CITED family, formerly called the MSG 1 family, function as transcriptional coregulators. By interacting with both sequence-specific transcription factors and CBP/p300, the CITED proteins affect CBP/p300-dependent transcription. Importantly, the coregulating activity of the CITED proteins show remarkable gene-specificity; binding of a CITED-interacting transcription factor to a promoter is necessary - but not sufficient - for recruitment of the CITED proteins to promoters. Since only three genes - TGF-a, c-MYC, and glycoprotein a-subunit gene - have been identified as CITED-regulated genes so far, our knowledge of biological roles and molecular mechanisms of functions of the CITED proteins is still very limited. Therefore, in this project, attempts will be made to identify more CITED-regulated genes and to elucidate biochemical basis of the gene-specific coregulating activity of the CITED proteins.
In Specific Aim 1. 1, to obtain insights into CITED-regulated genes, phenotypes of knockout mice lacking the cited genes (cited1, cited2, and cited4) will be examined. To identify candidate CITED-regulated genes, mRNA expression profiles of the affected tissues will be determined.
In Specific Aim 1. 2, to obtain clues for identifying novel CITED-regulated promoters, attempts will be made to isolate genomic DNA fragments that recruit the CITED proteins by chromatin immunoprecipitation.
In Specific Aim 1. 3, roles of CITED4 in transcription of three candidate CITED4-regulated genes will be examined. Amounts of the mRNA transcripts of those candidates increased along with induced overexpression of CITED4 in human osteosarcoma cells. Attempts will be made to demonstrate direct involvement of CITED4 in transcriptional activation of these genes by cell culture-based analyses: reporter assays and chromatin immunoprecipitation. Physiological roles of CITED4 in their regulation will be evaluated using cited4 knockout mice. Finally, in Specific Aim 2, recruitment and modifications of protein factors to known CITED 1-regulated promoters in cultured cells will be examined by chromatin immunoprecipitation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082230-05
Application #
6640384
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Mietz, Judy
Project Start
1999-07-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
5
Fiscal Year
2003
Total Cost
$325,240
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Yang, Dehong; Guo, Jun; Divieti, Paola et al. (2008) CBP/p300-interacting protein CITED1 modulates parathyroid hormone regulation of osteoblastic differentiation. Endocrinology 149:1728-35
Yi, Xianhua; Bouley, Richard; Lin, Herbert Y et al. (2007) Alix (AIP1) is a vasopressin receptor (V2R)-interacting protein that increases lysosomal degradation of the V2R. Am J Physiol Renal Physiol 292:F1303-13
Howlin, J; McBryan, J; Napoletano, S et al. (2006) CITED1 homozygous null mice display aberrant pubertal mammary ductal morphogenesis. Oncogene 25:1532-42
Shioda, Toshi; Chesnes, Jessica; Coser, Kathryn R et al. (2006) Importance of dosage standardization for interpreting transcriptomal signature profiles: evidence from studies of xenoestrogens. Proc Natl Acad Sci U S A 103:12033-8
Rodriguez, Tristan A; Sparrow, Duncan B; Scott, Annabelle N et al. (2004) Cited1 is required in trophoblasts for placental development and for embryo growth and survival. Mol Cell Biol 24:228-44
Hur, Jingyung; Chesnes, Jessica; Coser, Kathryn R et al. (2004) The Bik BH3-only protein is induced in estrogen-starved and antiestrogen-exposed breast cancer cells and provokes apoptosis. Proc Natl Acad Sci U S A 101:2351-6
Coser, Kathryn R; Chesnes, Jessica; Hur, Jingyung et al. (2003) Global analysis of ligand sensitivity of estrogen inducible and suppressible genes in MCF7/BUS breast cancer cells by DNA microarray. Proc Natl Acad Sci U S A 100:13994-9
Yahata, Tetsuro; Takedatsu, Hiroko; Dunwoodie, Sally L et al. (2002) Cloning of mouse Cited4, a member of the CITED family p300/CBP-binding transcriptional coactivators: induced expression in mammary epithelial cells. Genomics 80:601-13
Yahata, T; Shao, W; Endoh, H et al. (2001) Selective coactivation of estrogen-dependent transcription by CITED1 CBP/p300-binding protein. Genes Dev 15:2598-612
Sado, T; Fenner, M H; Tan, S S et al. (2000) X inactivation in the mouse embryo deficient for Dnmt1: distinct effect of hypomethylation on imprinted and random X inactivation. Dev Biol 225:294-303

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