SnoN activates p53 directly to regulate aging and tumorigenesis.
We have identified SnoN as a direct activator of p53 to accelerate aging and inhibit tumorigenesis. SnoN has been shown previously to promote proliferation and transformation by antagonizing TGFβ signaling. We show that elimination of this TGFβ antagonistic activity of SnoN in vivo results in accelerated aging and resistance to tumorigenesis. The SnoN knockin mice display a shortened lifespan, decreased reproductivity, osteoporosis, reduced regenerative capacity, and other aging phenotypes, similar to that found in mice expressing an active p53. These activities of SnoN rely on the ability of SnoN to activate p53. SnoN can bind directly to p53 and compete with Mdm2 for binding to p53, preventing p53 ubiquitination and degradation and additionally facilitating p53 acetylation and phosphorylation. SnoN also binds to p53 on the promoter of p53 responsive genes to promote transcription activation. This activation of p53 by SnoN is necessary for its antitumorigenic and progeria activities in vivo because elimination of one copy of p53 reverses the aging phenotypes and accelerates tumorigenesis. Thus, we have revealed a novel function of SnoN in regulating aging and tumorigenesis by directly activating p53.
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
Deng
D
Pan
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
Qingwei
Q
Zhu
Department of Bioengineering and QB3 University of California, Berkeley, CA 94720.
Michael J
MJ
Conboy
Department of Bioengineering and QB3 University of California, Berkeley, CA 94720.
Irina M
IM
Conboy
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
Kunxin
K
Luo
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D011518:Proto-Oncogene Proteins; C486157:Skil protein, mouse; D016159:Tumor Suppressor Protein p53; D004247:DNA; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2