Restoration of DNA-binding and growth-suppressive activity of mutant forms of p53 via a PCAF-mediated acetylation pathway.
Tumor-derived mutant forms of p53 compromise its DNA binding, transcriptional, and growth regulatory activity in a manner that is dependent upon the cell-type and the type of mutation. Given the high frequency of p53 mutations in human tumors, reactivation of the p53 pathway has been widely proposed as beneficial for cancer therapy. In support of this possibility p53 mutants possess a certain degree of conformational flexibility that allows for re-induction of function by a number of structurally different artificial compounds or by short peptides. This raises the question of whether physiological pathways for p53 mutant reactivation also exist and can be exploited therapeutically. The activity of wild-type p53 is modulated by various acetyl-transferases and deacetylases, but whether acetylation influences signaling by p53 mutant is still unknown. Here, we show that the PCAF acetyl-transferase is down-regulated in tumors harboring p53 mutants, where its re-expression leads to p53 acetylation and to cell death. Furthermore, acetylation restores the DNA-binding ability of p53 mutants in vitro and expression of PCAF, or treatment with deacetylase inhibitors, promotes their binding to p53-regulated promoters and transcriptional activity in vivo. These data suggest that PCAF-mediated acetylation rescues activity of at least a set of p53 mutations. Therefore, we propose that dis-regulation of PCAF activity is a pre-requisite for p53 mutant loss of function and for the oncogenic potential acquired by neoplastic cells expressing these proteins. Our findings offer a new rationale for therapeutic targeting of PCAF activity in tumors harboring oncogenic versions of p53.
Perez
Ricardo E
RE
Department of Oncology, School of Medicine, Georgetown University, Lombardi Comprehensive Cancer Center, Washington, District of Columbia 20057, USA.
Knights
Chad D
CD
Sahu
Geetaram
G
Catania
Jason
J
Kolukula
Vamsi K
VK
Stoler
Daniel
D
Graessmann
Adolf
A
Ogryzko
Vasily
V
Pishvaian
Michael
M
Albanese
Christopher
C
Avantaggiati
Maria Laura
ML
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009154:Mutation; D011485:Protein Binding; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D002843:Chromatin; D004247:DNA; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor