fig3

Figure 3. Wtp53 inactivation by genetic mutations and dominant negative p53 family proteins. The wtp53, once activated, works as a tetramer to bind the p53-regulatory elements (p53RE) of its direct target genes and induce transcription. At a late stage of tumor cells evolution mutant p53 forms tetramers and/or aggregates that are unable to bind to canonical target sequences to turn on its targets (LOF) (upper left panel). Some mutant p53 (p53R175H, p53R248Q, p53R273H) acquire novel gain of functions (GOFs) to activate (or repress) transcription independently of their binding to p53RE by cooperating with other transcription factors, such as NF-Y, ETS2 or NFkB, and drive the growth, survival and invasion of tumor cells. At earlier stages, when one allele is mutated there is reduced overall function resulting in haploinsufficieny and also the DNE of the mutant p53 on the wtp53 due to the formation of transcriptionally inactive heterotetramers (upper right panel). The N-terminal truncated isoforms (ΔTA or ΔN) of p53, p63 and p73 also exert a DNE on the wtp53. ΔN-tetramers compete with p53, TAp63 and TAp73 on the same p53RE leading to the abrogation of the wtp53 transcriptional program (middle and lower right panels)