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- Title
Impairment of p53 acetylation, stability and function by an oncogenic transcription factor.
- Authors
Alessandra Insinga, Filippo; Silvia Monestiroli, Filippo; Ronzoni, Simona; Carbone, Roberta; Pearson, Mark; Pruner, Guancarlo; Viale, Guuseppe; Appella, Ettore; Pelicci, PierGiuseppe; Saverio Minucci, PierGiuseppe
- 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.
- Publication
EMBO Journal, 2004, Vol 23, Issue 5, p1144
- ISSN
0261-4189
- Publication type
Academic Journal
- DOI
10.1038/sj.emboj.7600109