Article
- The EMBO Journal (2004) 23, 1144 - 1154
- doi:10.1038/sj.emboj.7600109
Published online: 19 February 2004
Subject Categories:
Impairment of p53 acetylation, stability and function by an oncogenic transcription factor
Alessandra Insinga1, Silvia Monestiroli1,4, Simona Ronzoni1, Roberta Carbone1, Mark Pearson1,a, Giancarlo Pruneri2, Giuseppe Viale2, Ettore Appella3, PierGiuseppe Pelicci1,4 and Saverio Minucci1,5
- Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
- Department of Pathology, European Institute of Oncology, Milan, Italy
- Laboratory of Cell Biology, National Cancer Institute, Bethesda MD, USA
- IFOM-FIRC Institute, Via Serio, Milan, Italy
- Department of Biomolecular Sciences and Biotechnologies, University of Milan, Via Celoria 26, Milan, Italy
Correspondence to:
PierGiuseppe Pelicci, Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Tel.: + +39 02 57489838; Fax: + +39 02 57489851; E-mail: pgpelicci@ieo.it
Saverio Minucci, Tel.: + +39 02 57489835; Fax: + +39 02 57489851; E-mail: sminucci@ieo.it
aPresent address: Novartis Laboratories, Basel, Switzerland
Received 8 August 2003; Accepted 8 January 2004
Abstract
Mutations of p53 are remarkably rare in acute promyelocytic leukemias (APLs). Here, we demonstrate that the APL-associated fusion proteins PML–RAR and PLZF-RAR directly inhibit p53, allowing leukemic blasts to evade p53-dependent cancer surveillance pathways. PML–RAR causes deacetylation and degradation of p53, resulting in repression of p53 transcriptional activity, and protection from p53-dependent responses to genotoxic stress. These phenomena are dependent on the expression of wild-type PML, acting as a bridge between p53 and PML–RAR. Recruitment of histone deacetylase (HDAC) to p53 and inhibition of p53 activity were abrogated by conditions that either inactivate HDACs or trigger HDAC release from the fusion protein, implicating recruitment of HDAC by PML–RAR as the mechanism underlying p53 inhibition.
Keywords:
- histone deacetylase,
- p53,
- PML,
- PML–RAR,
- promyelocytic leukemia
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