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

Abstract

The gene Trp53 is among the most frequently mutated and studied genes in human cancer, but the mechanisms by which it suppresses tumour formation remain unclear. We generated mice with an allele encoding changes at Leu25 and Trp26, known to be essential for transcriptional transactivation and Mdm2 binding, to enable analyses of Trp53 structure and function in vivo. The mutant Trp53 was abundant, its level was not affected by DNA damage and it bound 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 prone to tumours. We conclude that the determining pathway for Trp53 tumour-suppressor function in mice requires the transactivation domain.

C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage

“…[1][2][3][4][5] The ability of p53 to act as a transcriptional activator is thought to be important for the induction of apoptosis, since mutant p53 proteins that are defective in transcriptional activation fail to promote apoptosis of cells experiencing DNA damage. 6,7 Numerous transcriptional targets of p53 have been described. Among these are several cell death genes including Bax, Apaf-1, Pidd, and two BH3 (Bcl-2 homology region 3)-only genes, PUMA and Noxa.…”

Activation and activities of the p53 tumour suppressor protein

“…Cells in which the wild-type p53 was replaced by a transcriptionally inactive mutant showed loss of both cell cycle arrest and apoptotic functions, supporting the importance of transcriptional regulation in these responses (Chao et al, 2000;Jimenez et al, 2000).…”

Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4

“…Consistent with the recent data described above, specific expression of p53 in neuronal progenitor cells and postmitotic neurons of mice lacking mdm2 lead to accumulation of p53. 28 Mdm2 FM (41) 29,30 Similarly, a p53 mutant lacking the proline-rich domain (p53 DP ), a region that appears to modulate Mdm2 binding and Mdm2-mediated degradation in vitro, 31,32 indeed exhibits a significantly shorter half-life than wild-type p53 in vivo (Toledo et al, unpublished data).…”