Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression.
Cell. 2011 May 13; 145(4):571-83
This is an exciting story reporting that minimal transactivation activity of p53, although it is not sufficient to induce G1 arrest or apoptosis following DNA damage, is fully capable of suppressing tumorigenesis in vivo.
Tumor suppressor p53 acts as a transcriptional activator and is responsible for upregulating a long list of genes involved in cell-cycle control, apoptosis and other cellular processes following DNA damage and other stresses. However, it remains unclear which one or more of these functions of p53 is important for its tumor suppressor functions, since the p53 L25Q/W26S mutant still acts like a tumor suppressor, although it cannot induce cell-cycle arrest and is defective in promoting apoptosis. In this study, the authors generate a transcriptional dead mutant of p53 and demonstrate that the residual transcriptional activity of p53 in the L25Q/W26S mutant is responsible for its tumor suppressor functions. Moreover, they identify a set of genes that are regulated by this minimally active p53 L25Q/W26S mutant and show that these new p53 target genes have tumor suppressor activities. The next question is whether or not this new set of p53 target genes alone is sufficient to account for all of the p53 tumor suppressor functions. Alternatively, p53 tumor suppressor functions may require both of these novel p53-regulated genes, together with other previously identified p53 target genes.
Chen J: F1000Prime Recommendation of [Brady CA et al., Cell 2011, 145(4):571-83]. In F1000Prime, 07 Jun 2011; DOI: 10.3410/f.10999956.11938054. F1000Prime.com/10999956#eval11938054
F1000Prime Recommendations, Dissents and Comments for [Brady CA et al., Cell 2011, 145(4):571-83]. In F1000Prime, 05 Dec 2013; F1000Prime.com/10999956
The molecular basis for p53-mediated tumor suppression remains unclear. Here, to elucidate mechanisms of p53 tumor suppression, we use knockin mice expressing an allelic series of p53 transcriptional activation mutants. Microarray analysis reveals that one mutant, p53(25,26), is severely compromised for transactivation of most p53 target genes, and, moreover, p53(25,26) cannot induce G(1)-arrest or apoptosis in response to acute DNA damage. Surprisingly, p53(25,26) retains robust activity in senescence and tumor suppression, indicating that efficient transactivation of the majority of known p53 targets is dispensable for these pathways. In contrast, the transactivation-dead p53(25,26,53,54) mutant cannot induce senescence or inhibit tumorigenesis, like p53 nullizygosity. Thus, p53 transactivation is essential for tumor suppression but, intriguingly, in association with a small set of novel p53 target genes. Together, our studies distinguish the p53 transcriptional programs involved in acute DNA-damage responses and tumor suppression-a critical goal for designing therapeutics that block p53-dependent side effects of chemotherapy without compromising p53 tumor suppression.
Copyright © 2011 Elsevier Inc. All rights reserved.
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