The finite proliferative potential of normal human cells leads to replicative cellular senescence, which is a critical barrier to tumour progression in vivo1,2,3. We show that the human p53 isoforms Δ133p53 and p53β4 function in an endogenous regulatory mechanism for p53-mediated replicative senescence. Induced p53β and diminished Δ133p53 were associated with replicative senescence, but not oncogene-induced senescence, in normal human fibroblasts. The replicatively senescent fibroblasts also expressed increased levels of miR-34a, a p53-induced microRNA5,6,7,8,9, the antisense inhibition of which delayed the onset of replicative senescence. The siRNA (short interfering RNA)-mediated knockdown of endogenous Δ133p53 induced cellular senescence, which was attributed to the regulation of p21WAF1 and other p53 transcriptional target genes. In overexpression experiments, whereas p53β cooperated with full-length p53 to accelerate cellular senescence, Δ133p53 repressed miR-34a expression and extended the cellular replicative lifespan, providing a functional connection of this microRNA to the p53 isoform-mediated regulation of senescence. The senescence-associated signature of p53 isoform expression (that is, elevated p53β and reduced Δ133p53) was observed in vivo in colon adenomas with senescent phenotypes10,11. The increased Δ133p53 and decreased p53β isoform expression found in colon carcinoma may signal an escape from the senescence barrier during the progression from adenoma to carcinoma.
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We thank M. Serrano, M. Tainsky, M. Oshimura, G. Hannon, T. de Lange and J. Khan for cells and reagents, X. Wang for helpful discussions, E. Spillare for continuous support and E. Michalova for technical assistance. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute (NCI). B.V. was supported by the grants from the Grant Agency of the Czech Republic (GACR; number 301/08/1468) and the Internal Grant Agency of Health of Czech Republic (IGA MZ CR; number NS/9812-4). J.C.B. was supported by Breast Cancer Campaign, Cancer-Research UK (CRUK) and the Institut National de la Sante et de la Recherche Medicale (Inserm). D.L. is a Gibb fellow of CRUK. H. J. participated in the NIH Summer Internship Program.
The authors declare no competing financial interests.
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Fujita, K., Mondal, A., Horikawa, I. et al. p53 isoforms Δ133p53 and p53β are endogenous regulators of replicative cellular senescence. Nat Cell Biol 11, 1135–1142 (2009). https://doi.org/10.1038/ncb1928
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