A transactivation-deficient mouse model provides insights into Trp53 regulation and function

The gene Trp53 is among the most frequently mutated and studied genes in hu man cancer, but the mechanisms by which it suppresses tumour formation rema in unclear. We generated mice with an allele encoding changes at Leu25 and Trp26, known to be essential for transcriptional transactivation and Mdm2 b inding, to enable analyses of Trp53 structure and function in vivo. The mut ant Trp53 was abundant, its level was not affected by DNA damage and it bou nd DNA constitutively; however, it showed defects in cell-cycle regulation and apoptosis. Both mutant and Trp53-null mouse embryonic fibroblasts (MEFs ) were readily transformed by oncogenes, and the corresponding mice were pr one to tumours. We conclude that the determining pathway for Trp53 tumour-s uppressor function in mice requires the transactivation domain.