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Promyelocytic Leukaemia 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.


Choi WI, Yoon JH, Kim MY, Koh DI, Licht JD, Kim K, Hur MW

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 HDAC-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. 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 the 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.

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Published
May, 2014

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