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Promyelocytic Leukemia Zinc Finger-Retinoic Acid Receptor α (PLZF-RARα), an Oncogenic Transcriptional Repressor of Cyclin-dependent Kinase Inhibitor 1A (p21WAF/CDKN1A) and Tumor Protein p53 (TP53) Genes

Authors
 Won-Il Choi  ;  Jae-Hyeon Yoon  ;  Min-Young Kim  ;  Dong-In Koh  ;  Jonathan D. Licht  ;  Kunhong Kim  ;  Man-Wook Hur 
Citation
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.289(27) : 18641-18656, 2014 
Journal Title
 JOURNAL OF BIOLOGICAL CHEMISTRY 
ISSN
 0021-9258 
Issue Date
2014
MeSH
Binding, Competitive ; Cell Line, Tumor ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p21/deficiency ; Cyclin-Dependent Kinase Inhibitor p21/genetics* ; DNA (Cytosine-5-)-Methyltransferases/metabolism ; DNA Methylation ; DNA-Binding Proteins/metabolism ; Epigenesis, Genetic ; Gene Silencing ; Histone Deacetylases/metabolism ; Histones/metabolism ; Humans ; Mi-2 Nucleosome Remodeling and Deacetylase Complex/metabolism ; Oncogene Proteins, Fusion/metabolism* ; Promoter Regions, Genetic/genetics ; Protein Stability ; Repressor Proteins/metabolism* ; S Phase ; Sp1 Transcription Factor/metabolism ; Transcription, Genetic/genetics* ; Tumor Suppressor Protein p53/genetics*
Keywords
Leukemia ; Oncogene ; PLZF-RAR ; Transcription Regulation ; Transcription Repressor ; p21WAF/CDKN1A ; p53
Abstract
Promyelocytic leukemia zinc finger-retinoic acid receptor α (PLZF-RARα) is an oncogene transcriptional repressor that is generated by a chromosomal translocation between the PLZF and RARα genes in acute promyelocytic leukemia (APL-type) patients. The molecular interaction between PLZF-RARα and the histone deacetylase corepressor was proposed to be important in leukemogenesis. We found that PLZF-RARα can repress transcription of the p21WAF/CDKN1A gene, which encodes the negative cell cycle regulator p21 by binding to its proximal promoter Sp1-binding GC-boxes 3, 4, 5/6, a retinoic acid response element (RARE), and distal p53-responsive elements (p53REs). PLZF-RARα also acts as a competitive transcriptional repressor of p53, RARα, and Sp1. PLZF-RARα interacts with co-repressors such as mSin3A, NCoR, and SMRT, thereby deacetylating histones Ac-H3 and Ac-H4 at the CDKN1A promoter. PLZF-RARα also interacts with the MBD3-NuRD complex, leading to epigenetic silencing of CDKN1A through DNA methylation. Furthermore, PLZF-RARα represses TP53 and increases p53 protein degradation by ubiquitination, further repressing p21 expression. Resultantly, PLZF-RARα promotes cell proliferation and significantly increases the number of cells in S-phase.
Full Text
http://www.jbc.org/content/289/27/18641.long
DOI
10.1074/jbc.M113.538777
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kun Hong(김건홍) ORCID logo https://orcid.org/0000-0001-5639-6372
Kim, Min Young(김민영)
Yoon, Jae Hyeon(윤재현)
Choi, Won Il(최원일)
Hur, Man Wook(허만욱) ORCID logo https://orcid.org/0000-0002-3416-1334
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/99039
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