Definition of a p53 transactivation function-deficient mutant and characterization of two independent p53 transactivation subdomains

The wild-type protein product of the p53 tumor suppressor gene can activate transcription of genes which are involved in mediating either growth arres t, e.g. WAF1 or apoptotis, e.g. BAX and PIG3. Additionally, p53 can repress a variety of promoters, which, in turn, may be responsible for the functio nal activities exhibited by p53. This study shows that the Q22, S23 double mutation, which is known to inactivate a p53 transactivation subdomain loca ted within the initial 40 residues of the protein, while abrogating transac tivation from the WAF1 promoter, only attenuates apoptosis triggering, tran sactivation from other p53-responsive promoters and repression of promoters by p53. The Q53, S54 double mutation, which inactivates another p53 transa ctivation subdomain situated between amino acids 43 and 73 results in atten uation of all of the aforementioned p53 activities. In contrast to the Q22, S23 double mutation, this latter mutation set does not alter mdm-2-mediate d inhibition and degradation of p53. Finally, mutation of all four residues results in complete abrogation of every p53 activity mentioned above.