p53 isoforms Delta 133p53 and p53 beta are endogenous regulators of replicative cellular senescence

Kaori Fujita, Abdul M. Mondal, Izumi Horikawa, Giang H. Nguyen, Kensuke Kumamoto, Jane J. Sohn, Elise D. Bowman, Ewy A. Mathe, Aaron J. Schetter, Sharon R. Pine, Helen Ji, Borivoj Vojtesek, Jean-Christophe Bourdon, David P. Lane, Curtis C. Harris

    Research output: Contribution to journalArticle

    190 Citations (Scopus)

    Abstract

    The finite proliferative potential of normal human cells leads to replicative cellular senescence, which is a critical barrier to tumour progression in vivo(1-3). We show that the human p53 isoforms Delta 133p53 and p53 beta(4) function in an endogenous regulatory mechanism for p53-mediated replicative senescence. Induced p53 beta and diminished Delta 133p53 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(5-9), the antisense inhibition of which delayed the onset of replicative senescence. The siRNA (short interfering RNA)-mediated knockdown of endogenous Delta 133p53 induced cellular senescence, which was attributed to the regulation of p21(WAF1) and other p53 transcriptional target genes. In overexpression experiments, whereas p53 beta cooperated with full-length p53 to accelerate cellular senescence, Delta 133p53 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 p53 beta and reduced Delta 133p53) was observed in vivo in colon adenomas with senescent phenotypes(10,11). The increased Delta 133p53 and decreased p53 beta isoform expression found in colon carcinoma may signal an escape from the senescence barrier during the progression from adenoma to carcinoma.

    Original languageEnglish
    Pages (from-to)1135-U208
    Number of pages24
    JournalNature Cell Biology
    Volume11
    Issue number9
    DOIs
    Publication statusPublished - Sep 2009

    Keywords

    • ONCOGENE-INDUCED SENESCENCE
    • HUMAN-COLON
    • DNA-DAMAGE
    • DOWNSTREAM TARGET
    • EXPRESSION
    • MIR-34A
    • CANCER
    • GENE
    • APOPTOSIS
    • CELLS

    Cite this

    Fujita, K., Mondal, A. M., Horikawa, I., Nguyen, G. H., Kumamoto, K., Sohn, J. J., Bowman, E. D., Mathe, E. A., Schetter, A. J., Pine, S. R., Ji, H., Vojtesek, B., Bourdon, J-C., Lane, D. P., & Harris, C. C. (2009). p53 isoforms Delta 133p53 and p53 beta are endogenous regulators of replicative cellular senescence. Nature Cell Biology, 11(9), 1135-U208. https://doi.org/10.1038/ncb1928