TY - JOUR
T1 - Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression
AU - Brady, Colleen A.
AU - Jiang, Dadi
AU - Mello, Stephano S.
AU - Johnson, Thomas M.
AU - Jarvis, Lesley A.
AU - Kozak, Margaret M.
AU - Broz, Daniela Kenzelmann
AU - Basak, Shashwati
AU - Park, Eunice J.
AU - McLaughlin, Margaret E.
AU - Karnezis, Anthony N.
AU - Attardi, Laura D.
N1 - Funding Information:
Microarray analyses were performed using BRB-ArrayTools developed by Dr. Richard Simon and the BRB-ArrayTools Development Team. We thank T. Jacks for providing the Rosa26CreER T2 mice, S. Lowe for the pWZL-HrasV12 plasmid and Pml antibody, S. Artandi for the 3xHA expression plasmid, and W. Hahn and A. Schinzel and the Dana Farber RNAi facility for the lentiviral shRNA constructs; D. Burkhart, A. Krieg, J. Sage, and L. Sayles for technical assistance; and S. Artandi, A. Brunet, A. Giaccia, and J. Sage for critical reading of the manuscript. This work was supported by a Smith Stanford Graduate Fellowship to C.A.B., a Lucille P. Markey Biomedical Research Stanford Graduate Fellowship to T.M.J., National Science Foundation Graduate Research Fellowships to C.A.B. and T.M.J., a Gerald Lieberman Dissertation Fellowship to C.A.B., a C.A.P.E.S Fellowship to S.S.M., a Swiss National Science Foundation Fellowship to D.K.B., and funding from the American Cancer Society, the Leukemia and Lymphoma Society, and the National Institutes of Health (CA140875) to L.D.A.
PY - 2011/5/13
Y1 - 2011/5/13
N2 - 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, p5325,26, is severely compromised for transactivation of most p53 target genes, and, moreover, p5325,26 cannot induce G1-arrest or apoptosis in response to acute DNA damage. Surprisingly, p5325,26 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 p5325,26,53,54 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.
AB - 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, p5325,26, is severely compromised for transactivation of most p53 target genes, and, moreover, p5325,26 cannot induce G1-arrest or apoptosis in response to acute DNA damage. Surprisingly, p5325,26 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 p5325,26,53,54 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.
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U2 - 10.1016/j.cell.2011.03.035
DO - 10.1016/j.cell.2011.03.035
M3 - Article
C2 - 21565614
AN - SCOPUS:79955795151
SN - 0092-8674
VL - 145
SP - 571
EP - 583
JO - Cell
JF - Cell
IS - 4
ER -