title: The proto-oncoprotein FBI-1 interacts with MBD3 to recruit the Mi-2/NuRD-HDAC complex and BCoR and to silence p21WAF/CDKN1A by DNA methylation.
abstract: The tumour-suppressor gene CDKN1A (encoding p21Waf/Cip1) is thought to be epigenetically repressed in cancer cells. FBI-1 (ZBTB7A) is a proto-oncogenic transcription factor repressing the alternative reading frame and p21WAF/CDKN1A genes of the p53 pathway. FBI-1 interacts directly with MBD3 (methyl-CpG-binding domain protein 3) in the nucleus. We demonstrated that FBI-1 binds both non-methylated and methylated DNA and that MBD3 is recruited to the CDKN1A promoter through its interaction with FBI-1, where it enhances transcriptional repression by FBI-1. FBI-1 also interacts with the co-repressors nuclear receptor corepressor (NCoR), silencing mediator for retinoid and thyroid receptors (SMRT) and BCL-6 corepressor (BCoR) to repress transcription. MBD3 regulates a molecular interaction between the co-repressor and FBI-1. MBD3 decreases the interaction between FBI-1 and NCoR/SMRT but increases the interaction between FBI-1 and BCoR. Because MBD3 is a subunit of the Mi-2 autoantigen (Mi-2)/nucleosome remodelling and histone deacetylase (NuRD)-HDAC complex, FBI-1 recruits the Mi-2/NuRD-HDAC complex via MBD3. BCoR interacts with the Mi-2/NuRD-HDAC complex, DNMTs and HP1. MBD3 and BCoR play a significant role in the recruitment of the Mi-2/NuRD-HDAC complex- and the NuRD complex-associated proteins, DNMTs and HP. By recruiting DNMTs and HP1, Mi-2/NuRD-HDAC complex appears to play key roles in epigenetic repression of CDKN1A by DNA methylation.
authors: Department of Biochemistry and Molecular Biology, BK21 Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50 Yonsei-Ro, SeoDaeMoon-Gu, Seoul, 120-752, Korea.
authors: Won-Il
authors: WI
authors: Choi
authors: Bu-Nam
authors: BN
authors: Jeon
authors: Jae-Hyeon
authors: JH
authors: Yoon
authors: Dong-In
authors: DI
authors: Koh
authors: Myung-Hwa
authors: MH
authors: Kim
authors: Mi-Young
authors: MY
authors: Yu
authors: Kyung-Mi
authors: KM
authors: Lee
authors: Youngsoo
authors: Y
authors: Kim
authors: Kyunggon
authors: K
authors: Kim
authors: Sujin Susanne
authors: SS
authors: Hur
authors: Choong-Eun
authors: CE
authors: Lee
authors: Kyung-Sup
authors: KS
authors: Kim
authors: Man-Wook
authors: MW
authors: Hur
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020868:Gene Silencing; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C411984:BCOR protein, human; C493956:CDKN1A protein, human; D002868:Chromosomal Proteins, Non-Histone; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D006657:Histones; C115369:MBD3 protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C485514:ZBTB7A protein, human; D000090266:Chromobox Protein Homolog 5; D004248:DNA (Cytosine-5-)-Methyltransferases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex
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