Physical interaction with human tumor-derived p53 mutants inhibits p63 activities.
The p53 tumor suppressor gene is the most frequent target for genetic alterations in human cancers, whereas the recently discovered homologues p73 and p63 are rarely mutated. We and others have previously reported that human tumor-derived p53 mutants can engage in a physical association with different isoforms of p73, inhibiting their transcriptional activity. Here, we report that human tumor-derived p53 mutants can associate in vitro and in vivo with p63 through their respective core domains. We show that the interaction with mutant p53 impairs in vitro and in vivo sequence-specific DNA binding of p63 and consequently affects its transcriptional activity. We also report that in cells carrying endogenous mutant p53, such as T47D cells, p63 is unable to recruit some of its target gene promoters. Unlike wild-type p53, the binding to specific p53 mutants markedly counteracts p63-induced growth inhibition. This effect is, at least partially, mediated by the core domain of mutant p53. Thus, inactivation of p53 family members may contribute to the biological properties of specific p53 mutants in promoting tumorigenesis and in conferring selective survival advantage to cancer cells.
Strano
Sabrina
S
Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Rome 00158, Italy.
Fontemaggi
Giulia
G
Costanzo
Antonio
A
Rizzo
Maria Giulia
MG
Monti
Olimpia
O
Baccarini
Alessia
A
Del Sal
Giannino
G
Levrero
Massimo
M
Sacchi
Ada
A
Oren
Moshe
M
Blandino
Giovanni
G
D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins; D016147:Genes, Tumor Suppressor; D006639:Histidine / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins; D009154:Mutation; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors; D014364:Tryptophan / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
C081876:CKAP4 protein, human; D017931:DNA Primers; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D006639:Histidine; D014364:Tryptophan; D004247:DNA