title: 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.
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.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Science Institute, Yonsei University School of Medicine, 50 Yonsei-Ro, SeoDaeMoon-Gu, Seoul 120-752, Korea and.
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Choi
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Science Institute, Yonsei University School of Medicine, 50 Yonsei-Ro, SeoDaeMoon-Gu, Seoul 120-752, Korea and.
authors.forename: Jae-Hyeon
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Science Institute, Yonsei University School of Medicine, 50 Yonsei-Ro, SeoDaeMoon-Gu, Seoul 120-752, Korea and.
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Kim
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Science Institute, Yonsei University School of Medicine, 50 Yonsei-Ro, SeoDaeMoon-Gu, Seoul 120-752, Korea and.
authors.forename: Dong-In
authors.initials: DI
authors.lastname: Koh
authors.affiliation: the Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Licht
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Science Institute, Yonsei University School of Medicine, 50 Yonsei-Ro, SeoDaeMoon-Gu, Seoul 120-752, Korea and.
authors.forename: Kunhong
authors.initials: K
authors.lastname: Kim
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Science Institute, Yonsei University School of Medicine, 50 Yonsei-Ro, SeoDaeMoon-Gu, Seoul 120-752, Korea and mwhur2@yuhs.ac.
authors.forename: Man-Wook
authors.initials: MW
authors.lastname: Hur
mesh_terms: D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D055550:Protein Stability; D012097:Repressor Proteins / Q000378:metabolism*; D016196:S Phase; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000099186:Histone Deacetylase 3
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D004248:DNA (Cytosine-5-)-Methyltransferases; D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D006657:Histones; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D015514:Oncogene Proteins, Fusion; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D016159:Tumor Suppressor Protein p53; D000099186:Histone Deacetylase 3; C115369:MBD3 protein, human; C118318:PLZF-RARalpha fusion protein, human
keywords: Leukemia; Oncogene; PLZF-RAR; Transcription Regulation; Transcription Repressor; p21WAF/CDKN1A; p53