The p53 tumour suppressor is a transcriptional factor whose activity is modulated by protein stability and post-translational modifications including acetylation1,2,3,4. The mechanism by which acetylated p53 is maintained in vivo remains unclear. Here we show that the deacetylation of p53 is mediated by an histone deacetylase-1 (HDAC1)-containing complex. We have also purified a p53 target protein in the deacetylase complexes (designated PID; but identical to metastasis-associated protein 2 (MTA2)), which has been identified as a component of the NuRD complex5,6,7. PID specifically interacts with p53 both in vitro and in vivo, and its expression reduces significantly the steady-state levels of acetylated p53. PID expression strongly represses p53-dependent transcriptional activation, and, notably, it modulates p53-mediated cell growth arrest and apoptosis. These results show that deacetylation and functional interactions by the PID/MTA2-associated NuRD complex may represent an important pathway to regulate p53 function.
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We thank R. Dalla-Favera, R. Baer and B. Tycko for critical discussions, and use of laboratory space and reagents; K. Vousden, B. Vogelstein, A. Levine, M. Oren, Y. Xiong, C. Hassig, S. L. Schreiber, S. Chellappan, G. Lozano and P. P. Pandolfi for antibodies, cell lines and plasmids; J. Qin, W. Wang and Y. Zhang for help; G. Cattoretti and H. Niu for suggestions in apoptosis assays; the sequencing facility of Columbia University Cancer Center for sequencing; F. Huang, M. Li, A. Nikolaev and N. A. Papanikolaou for sharing unpublished data and critical comment; and R.G. Roeder for continuous support and encouragement. This work was supported in part by grants from the NIH/NCI, the American Cancer Society and the Herbert Irving Comprehensive Cancer Center to W.G.
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Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (2019)
Temporal and differential regulation of KAISO-controlled transcription by phosphorylated and acetylated p53 highlights a crucial regulatory role of apoptosis
Journal of Biological Chemistry (2019)
International Journal of Molecular Sciences (2019)
Nature Reviews Molecular Cell Biology (2019)
The stoichiometry and interactome of the Nucleosome Remodeling and Deacetylase (NuRD) complex are conserved across multiple cell lines
The FEBS Journal (2019)