Abstract The finite proliferative potential of normal human cells leads to replicative cellular senescence, which is a critical barrier to tumor progression in vivo. The p53 signaling pathway plays central roles in the regulation of cellular senescence. Humans, as well as Drosophila and zebrafish, have p53 isoforms; however, their regulation and function are poorly understood. We here examine the expression profiles of two human p53 isoforms, p53β (lacking the C-terminal oligomerization domain due to an alternative mRNA splicing) and Δ133p53 (lacking the N-terminal transactivation and proline-rich domains due to the transcription from an alternative promoter in intron 4), during in vitro and in vivo cellular senescence and their biological activities in regulating cellular 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 microRNA, the antisense inhibition of which delayed the onset of replicative senescence. The siRNA-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, while p53β cooperated with full-length p53 to accelerate cellular senescence, Δ133p53 repressed miR-34a expression and extended 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 (i.e., elevated p53β and reduced Δ133p53) was observed in vivo in colon adenomas with senescent phenotypes. The decreased p53β and increased Δ133p53 expression found in colon carcinomas might signal an escape from the senescence barrier during the progression from premalignant to malignant tumors in vivo. This study shows that natural p53 isoforms constitute an endogenous regulatory mechanism for p53-mediated replicative senescence and may open up a new p53-based, senescence-mediated strategy to manipulate carcinogenesis and aging. The molecular details of the senescence-associated Δ133p53 repression and p53β induction are currently under investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2915.
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