Insights into Selective Activation of p53 DNA Binding by c-Abl

Abstract

As a transcription factor, p53 recognizes a specific consensus DNA sequence and activates the expression of the target genes involved in either growth arrest or apoptosis. Despite our wealth of knowledge on the genes that are targeted by p53 in growth arrest and apoptosis, relatively little is known about the promoter specificity triggered by p53 in these processes. Here we show that interaction with c-Abl stabilized p53 tetrameric conformation, and as a consequence c-Abl stimulated p53 DNA binding only when all quarter binding sites (a perfect binding sequence) on p53-responsive promoters were present. This result suggests that in response to DNA damage, c-Abl binding may specifically stimulate p53 DNA binding on the promoters with perfect binding sequences. A sequence comparison of several known p53-responsive elements illustrates the presence of the perfect binding sequences on the p21 but not the Bax promoter. Significantly, we show that c-Abl indeed enhanced p53 DNA binding and transcription from p21 but not Bax. These results suggest that the promoter specificity plays an important role in selective activation of p53 DNA binding by c-Abl. The implications of this with relation to selective activation of p53 target genes involved in either growth arrest or apoptosis are discussed.