Network Effect of Wt-mutant p53 Interactions and Implications on p53 Gene Therapy

Abstract

Mutant p53 could have either a dominant negative effect or a gain of function to interfere with p53's ability to maintain genomic stability. In the present study, we screened for TP53 mutations in hepatocellular carcinoma (HCC) samples from 202 Chinese patients, followed by analysis of transcriptional and apoptotic activities of 21 p53 mutants with or without wild-type p53 present. We identified a new point mutation p.P72A, and a mutation (p.E294SfsX51) with a record long frameshift. We found TP53 mutations in HCC bear mutants without a dominant wild-type p53 inhibition on p21 transcription at a higher frequency. We found an anti-correlation for p53 WT/mutant heterotetramer to activate p21 and BAX transcription, i.e., at given p53 WT/mutant concentration, the fold increase p21 transcription is proportional to the fold of decreasing BAX transcription. Our kinetic model reproduced the trend in the experimental observation and confirmed that the p53 WT-dimer/mutant- heterotetramer is the major species to confer the differential activation of p21 and BAX transcription. p53 may have different binding modes on p21 and BAX, most likely resulting from the combinational effects of core domain binding and C-terminal mediation. Our study demonstrated that p53 mutants interfere with the ability of WT p53 to maintain genomic stability.