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.

Impairment of p53 acetylation, stability and function by an oncogenic transcription factor / A. Insinga, S. Monestiroli, S. Ronzoni, R. Carbone, M. Pearson, G. Pruneri, G. Viale, E. Appella, P. Pelicci, S. Minucci. - In: EMBO JOURNAL. - ISSN 0261-4189. - 23:5(2004), pp. 1144-1154.

Impairment of p53 acetylation, stability and function by an oncogenic transcription factor

G. Pruneri;G. Viale;P. Pelicci
Penultimo
;
S. Minucci
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.
histone deacetylase ; p53 ; PML ; PML–RAR ; promyelocytic leukemia
Settore MED/04 - Patologia Generale
Settore MED/08 - Anatomia Patologica
2004
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/51183
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