Change of conformation of the DNA-binding domain of p53 is the only key element for binding of and interference with p73.
Xenopus p53 has biological and biochemical properties similar to those of human p53, except for optimal temperature. The frog protein is fully active at 30 degrees C and inactive at 37 degrees C, leading to a temperature-sensitive behavior similar to that of the human mutant p53Ala(143) and the murine mutant p53Val(135). Using hybrid proteins between human and Xenopus expressed from artificial p53 minigenes, we have been able to demonstrate that change of conformation of the DNA-binding domain is the major determinant of this heat sensitivity. It has been reported that some human tumor-derived p53 mutants can engage in a physical association with p73, thus inhibiting its transactivating properties. The mechanism of this association remains to be elucidated. The nature of the mutant p53 that can engage in this association also remains controversial. Using the unique opportunity of the temperature sensitivity of Xenopus p53, we demonstrate that binding of and interference with p73 require a change of conformation in the p53 protein. This interaction occurs through the DNA-binding domain of p53 only when it is in a denatured state. These results reinforce the notion that mutant p53 with a conformational change can act as a down-regulator of the p73 pathway in human cancer and could confer a selective advantage to the tumor.
Bensaad
Karim
K
Laboratoire de génotoxicologie des tumeurs, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
Le Bras
Morgane
M
Unsal
Keziban
K
Strano
Sabrina
S
Blandino
Giovanni
G
Tominaga
Osamu
O
Rouillard
Dany
D
Soussi
Thierry
T
D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D013696:Temperature; D014158:Transcription, Genetic; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D014981:Xenopus
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004247:DNA