Tumour associated mutants of p53 can inhibit transcriptional activity of p53 without heterooligomerization

Abstract

Tumour suppressor protein p53 is the most frequent target of mutations occurring in different types of human cancers. Most of these are point mutations clustered in certain `hot spots'. Because p53 is a tetramer in solution, it can form heterooligomers when both wild-type and mutant forms of p53 are expressed in the same cell. Inactivation of wt p53 by heterooligomerization has been proposed as a mechanism for dominant negative effect of mutant protein. In this paper we show that other mechanisms can also be involved in the inhibition of transcriptional activity of wt p53 by mutant proteins. In addition to suppressing the wt p53 activity, mutant proteins are also able to suppress the activity of p53 protein unable to oligomerize. Either N- or C-terminus of mutant p53 are needed for this activity. The suppression of transcriptional activity described is restricted to p53-dependent promoters and no effect is seen with the promoter not containing p53 binding site. Point mutants also inhibit the growth suppressing activity of monomeric p53. Our data allow to propose the existence of a cofactor specifically needed for p53-dependent transcription. Depletion of this cofactor could be an alternative mechanism of inactivation of wt p53 by its point mutants.