Disruption of functions of wild-type p53 by hetero-oligomerization

We report that a p53 segment (p53 del 1-293) containing the oligomerization domain interferes with the functions of wild-type p53. Wild-type p53 inhib its transcription mediated by human cytomegalovirus (CMV) immediate-early p romoter significantly; however, co-expression of p53 del 1-293 drastically reduces this repression. We show that wild-type p53 forms hetero-oligomers with p53 del 1-293 suggesting that the hetero-oligomers are defective in re pressing the CMV promoter. A synthetic promoter with p53-binding sites is t ransactivated significantly by wild-type p53. However, co-expression of p53 del 1-293 drastically reduces this activation. At a high concentration, a deletion mutant of wild-type p53 (del 393-327) defective in oligomerization transactivates efficiently a promoter with synthetic p53-binding sites. Th is transactivation remains unaffected by coexpression of p53 del 1-293, p53 del 393-327 also fails to hetero-oligomerize with p53 del 1-293 indicating that hetero-oligomerization is necessary for disruption of wild-type p53-m ediated transactivation. Immunostaining experiments show that hetero-oligom elization does not lead to changes in localization of nuclear p53 demonstra ting that delocalization of p53 is not the reason for inactivation. We also show that co-expression of p53 del 1-293 significantly reduces the G1/S ar rest by wild-type p53 suggesting that a proper oligomeric form is necessary for wild-type p53-mediated cell cycle arrest. Thus, our work shows that he tero-oligomerization disrupts wild-type p53's biological functions and sugg ests a mechanism hv which 'dominant negative' p53 mutants may disrupt funct ions of wild-type p53.