UC San Diego

Previous work in determining the connection between p53 hyperactivity and premature aging has yielded conflicting results. By introducing aspartic acid mutations on sites Threonine 21 and Serine 23, hyperactivity of p53 was analyzed for its transcriptional activity of various target genes and subsequent physiological influences on cellular response. Target gene expressions show elevation in hyperactive heterozygous T21S23/D mutants in comparison to wild-type mice. Additionally, p53T21S23D/- mutant mice display signs of stem cell depletion, stagnant cell regeneration, organismal atrophy and degeneration as seen normally in aging. P53T21S23D/- mutant mice exhibit reduced lifespan surviving less than 2 months. Aging- inducing cellular responses such as apoptosis, cellular senescence and cell cycle arrest occurring only post to genotoxic stresses were suggested taking place in these super-active p53 mice models even without DNA damage. Furthermore, knock-out of p53 target gene PAI-1 failed to rescue homozygous T21S23/D mutant embryonic lethality. Taken together, it is concluded that hyperactivity of p53 through T21S23/D mutation leads to age-related phenotypes in mice models