Amino-terminal transactivation subdomains of p53 contribute equally to p53-induced gene expression

Jennifer M Smith, Université D'Ottawa / University Of Ottawa, Université D'Ottawa / University Of Ottawa
The p53 tumour suppressor is mutated in over 50% of sporadic cancers. Its tumour suppressive functions arise in large part from transcriptional activation of target genes. Two adjacent regions within the transactivation domain of p53 are sufficient to support sequence-specific transactivation when fused to a heterologous DNA binding domain. It has been hypothesized that these two subdomains of p53 may contribute to the expression of distinct p53-responsive genes and regulate distinct biological
more » ... pathways. In order to examine the subdomain requirements during transactivation, we used oligonucleotide microarrays to identify transcripts induced by variants of p53 with point mutations within subdomains 1, 2, or both (QS1, QS2, and QS1/QS2, respectively). Expression of wild type p53 (P53WT) statistically induced 254 transcripts and apoptosis transcripts (GO#0006915) were the only statistically over represented group. Most of these transcripts were poorly induced by the p53 variants and there was a corresponding decrease in the ability of these variants to induce apoptosis. Strikingly, several well known p53-regulated transcripts including TNFRSF10B, BTG2, and POLH were increased to wild type levels by p53QS1 and p53QS2 but not p53QS1/QS2, indicating that either subdomain1 or 2 is sufficient for p53-dependent expression of a small subset of p53-responsive genes. Unexpectedly, there was no evidence for p53QS1- or p53 QS2-specific gene expression. Taken together, these results demonstrated heterogeneity in the requirement for transactivation subdomains 1 and 2 of p53 without subdomain-specific contributions to p53-induced gene expression. The MafB transcript was identified as a p53WT -induced transcript that was not statistically increased in response to either p53QS1 or p53QS2 expression. Nonetheless, MafB expression increased more in response to the QS2 compared to the QS1 variant of p53 so MafB was studied further as a potential p53 target gene exhibiting a QS2-specific pattern of expression. Expression of p53WT increa [...]
doi:10.20381/ruor-19955 fatcat:m7vc5to4wfbttljnbartfqf5ze