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

被引:102
作者
Insinga, A
Monestiroli, S
Ronzoni, S
Carbone, R
Pearson, M
Pruneri, G
Viale, G
Appella, E
Pelicci, P
Minucci, S
机构
[1] European Inst Oncol, Dept Expt Oncol, I-20141 Milan, Italy
[2] European Inst Oncol, Dept Pathol, I-20141 Milan, Italy
[3] NCI, Cell Biol Lab, Bethesda, MD 20892 USA
[4] IFOM FIRC Inst, Milan, Italy
[5] Univ Milan, Dept Biomol Sci & Biotechnol, Milan, Italy
关键词
histone deacetylase; p53; PML; PML-RAR; promyelocytic leukemia;
D O I
10.1038/sj.emboj.7600109
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1144 / 1154
页数:11
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