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Impairment of p53 acetylation, stability and function by an oncogenic transcription factor
Author(s) -
Insinga Alessandra,
Monestiroli Silvia,
Ronzoni Simona,
Carbone Roberta,
Pearson Mark,
Pruneri Giancarlo,
Viale Giuseppe,
Appella Ettore,
Pelicci PierGiuseppe,
Minucci Saverio
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600109
Subject(s) - biology , acetylation , histone deacetylase , psychological repression , transcription factor , histone , cancer research , fusion protein , hdac1 , microbiology and biotechnology , genetics , gene expression , gene , recombinant dna
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.