FUNCTIONAL DOMAINS OF WILD-TYPE AND MUTANT P53 PROTEINS INVOLVED IN TRANSCRIPTIONAL REGULATION, TRANSDOMINANT INHIBITION, AND TRANSFORMATION SUPPRESSION

The wild-type (wt) p53 protein has transcriptional activation function s which may be linked to its tumor suppressor activity. Many mutant p5 3 proteins expressed in cancers have lost the ability to function as t ranscriptional activators and furthermore may inhibit wt p53 function. To study the mechanisms by which mutant forms of p53 have lost their transactivation function and can act in a dominant negative manner, a structure-function analysis of both mutant and engineered truncated fo rms of p53 was carried out. We show that different mutant p53 proteins found in cancers vary in the ability to inhibit the transcriptional t ransactivation and specific DNA binding activities of wt human p53. Th is transdominant effect was mediated through the carboxy-terminal olig omerization region. The role of the transactivation activity in transf ormation suppression by wt p53 was also examined by constructing an N- terminal deletion mutant lacking the transactivation domain. This muta nt was unable to transactivate but could bind specifically to DNA. Alt hough it was impaired in its ability to suppress transformation of pri mary rat embryo fibroblasts by adenovirus E1A plus activated ras, the N-terminal deletion mutant still had some suppression activity, sugges ting that additional functions of p53 may contribute to transformation suppression.