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Impairment of p53 acetylation, stability and function by an oncogenic transcription factor.
- Source :
-
The EMBO journal [EMBO J] 2004 Mar 10; Vol. 23 (5), pp. 1144-54. Date of Electronic Publication: 2004 Feb 19. - Publication Year :
- 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.
- Subjects :
- Acetylation
Alleles
Animals
Cell Line
DNA-Binding Proteins metabolism
Histone Deacetylases metabolism
Kruppel-Like Transcription Factors
Mice
Promyelocytic Leukemia Protein
Promyelocytic Leukemia Zinc Finger Protein
Proteasome Endopeptidase Complex metabolism
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-mdm2
Receptors, Retinoic Acid metabolism
Retinoic Acid Receptor alpha
Transcription, Genetic genetics
Tumor Suppressor Protein p53 antagonists & inhibitors
Tumor Suppressor Protein p53 deficiency
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Proteins
Neoplasm Proteins metabolism
Nuclear Proteins metabolism
Transcription Factors metabolism
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0261-4189
- Volume :
- 23
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The EMBO journal
- Publication Type :
- Academic Journal
- Accession number :
- 14976551
- Full Text :
- https://doi.org/10.1038/sj.emboj.7600109