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Proto-oncogene FBI-1 represses transcription of p21CIP1 by inhibition of transcription activation by p53 and Sp1

 Won-Il Choi  ;  Bu-Nam Jeon  ;  Chae-Ok Yun  ;  Pyung-Hwan Kim  ;  Sung-Eun Kim  ;  Kang-Yell Choi  ;  Se Hoon Kim  ;  Man-Wook Hur 
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.284(19) : 12633-12644, 2009 
Journal Title
Issue Date
Blotting, Western ; Bone Neoplasms/genetics ; Bone Neoplasms/metabolism ; Bone Neoplasms/pathology ; Cell Cycle ; Cell Proliferation ; Chromatin Immunoprecipitation ; Colony-Forming Units Assay ; Cyclin-Dependent Kinase Inhibitor p21/antagonists & inhibitors ; Cyclin-Dependent Kinase Inhibitor p21/genetics* ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; DNA-Binding Proteins/physiology* ; Electrophoretic Mobility Shift Assay ; Flow Cytometry ; Gene Expression Regulation, Neoplastic* ; HeLa Cells ; Humans ; Immunoprecipitation ; Mutagenesis, Site-Directed ; Osteosarcoma/genetics ; Osteosarcoma/metabolism ; Osteosarcoma/pathology ; Promoter Regions, Genetic ; RNA, Small Interfering/pharmacology ; Sp1 Transcription Factor/genetics* ; Transcription Factors/physiology* ; Transcription, Genetic/drug effects* ; Transcriptional Activation/drug effects* ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/genetics*
Aberrant transcriptional repression through chromatin remodeling and histone deacetylation has been postulated as the driving force for tumorigenesis. FBI-1 (formerly called Pokemon) is a member of the POK family of transcriptional repressors. Recently, FBI-1 was characterized as a critical oncogenic factor that specifically represses transcription of the tumor suppressor gene ARF, potentially leading indirectly to p53 inactivation. Our investigations on transcriptional repression of the p53 pathway revealed that FBI-1 represses transcription of ARF, Hdm2 (human analogue of mouse double minute oncogene), and p21CIP1 (hereafter indicated as p21) but not of p53. FBI-1 showed a more potent repressive effect on p21 than on p53. Our data suggested that FBI-1 is a master controller of the ARF-Hdm2-p53-p21 pathway, ultimately impinging on cell cycle arrest factor p21, by inhibiting upstream regulators at the transcriptional and protein levels. FBI-1 acted as a competitive transcriptional repressor of p53 and Sp1 and was shown to bind the proximal Sp1-3 GC-box and the distal p53-responsive elements of p21. Repression involved direct binding competition of FBI-1 with Sp1 and p53. FBI-1 also interacted with corepressors, such as mSin3A, NCoR, and SMRT, thereby deacetylating Ac-H3 and Ac-H4 histones at the promoter. FBI-1 caused cellular transformation, promoted cell cycle proliferation, and significantly increased the number of cells in S phase. FBI-1 is aberrantly overexpressed in many human solid tumors, particularly in adenocarcinomas and squamous carcinomas. The role of FBI-1 as a master controller of the p53 pathway therefore makes it an attractive therapeutic target.
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1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
5. Research Institutes (연구소) > Institute for Cancer Research (암연구소) > 1. Journal Papers
Yonsei Authors
Kim, Se Hoon(김세훈) ORCID logo https://orcid.org/0000-0001-7516-7372
Kim, Pyung Hwan(김평환)
Yun, Chae Ok(윤채옥)
Jeon, Bu Nam(전부남)
Choi, Won Il(최원일)
Hur, Man Wook(허만욱) ORCID logo https://orcid.org/0000-0002-3416-1334
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