Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 571-583 |
| Number of pages | 13 |
| Journal | Cell |
| Volume | 145 |
| Issue number | 4 |
| DOIs | |
| State | Published - May 13 2011 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression. / Brady, Colleen A.; Jiang, Dadi; Mello, Stephano S.; Johnson, Thomas M.; Jarvis, Lesley A.; Kozak, Margaret M.; Broz, Daniela Kenzelmann; Basak, Shashwati; Park, Eunice J.; McLaughlin, Margaret E.; Karnezis, Anthony; Attardi, Laura D.
In: Cell, Vol. 145, No. 4, 13.05.2011, p. 571-583.Research output: Contribution to journal › Article
}
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
AU - Attardi, Laura D.
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.
UR - http://www.scopus.com/inward/record.url?scp=79955795151&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79955795151&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2011.03.035
DO - 10.1016/j.cell.2011.03.035
M3 - Article
VL - 145
SP - 571
EP - 583
JO - Cell
JF - Cell
SN - 0092-8674
IS - 4
ER -