∆N-P63α and TA-P63α exhibit intrinsic differences in transactivation specificities that depend on distinct features of DNA target sites.

TP63 is a member of the TP53 gene family that encodes for up to ten different TA
and ∆N isoforms through alternative promoter usage and alternative splicing.
Besides being a master regulator of gene expression for squamous epithelial
proliferation, differentiation and maintenance, P63, through differential
expression of its isoforms, plays important roles in tumorigenesis. All P63
isoforms share an immunoglobulin-like folded DNA binding domain responsible for
binding to sequence-specific response elements (REs), whose overall consensus
sequence is similar to that of the canonical p53 RE. Using a defined assay in
yeast, where P63 isoforms and RE sequences are the only variables, and gene
expression assays in human cell lines, we demonstrated that human TA- and ∆N-P63α
proteins exhibited differences in transactivation specificity not observed with
the corresponding P73 or P53 protein isoforms. These differences 1) were
dependent on specific features of the RE sequence, 2) could be related to
intrinsic differences in their oligomeric state and cooperative DNA binding, and
3) appeared to be conserved in evolution. Since genotoxic stress can change
relative ratio of TA- and ∆N-P63α protein levels, the different transactivation
specificity of each P63 isoform could potentially influence cellular responses to
specific stresses.