Aging-associated truncated form of p53 interacts with wild-type p53 and alters p53 stability, localization, and activity

Mech Ageing Dev. 2007 Nov-Dec;128(11-12):717-30. doi: 10.1016/j.mad.2007.10.011. Epub 2007 Nov 1.

Abstract

Evidence has accumulated that p53, a prototypical tumor suppressor, may also influence aspects of organismal aging. We have previously described a p53 mutant mouse model, the p53+/m mouse, which is cancer resistant yet exhibits reduced longevity and premature aging phenotypes. p53+/m mice express one full length p53 allele and one truncated p53 allele that is translated into a C-terminal fragment of p53 termed the M protein. The augmented cancer resistance and premature aging phenotypes in the p53+/m mice are consistent with a hyperactive p53 state. To determine how the M protein could increase p53 activity, we examined the M protein in various cellular contexts. Here, we show that embryo fibroblasts from p53+/m mice exhibit reduced proliferation and cell cycle progression compared to embryo fibroblasts from p53+/- mice (with equivalent wild-type p53 dosage). The M protein interacts with wild-type p53, increases its stability, and facilitates its nuclear localization in the absence of stress. Despite increasing p53 stability, the M protein does not disrupt p53-Mdm2 interactions and does not prevent p53 ubiquitination. These results suggest molecular mechanisms by which the M protein could influence the aging and cancer resistance phenotypes in the p53+/m mouse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Aging / genetics
  • Aging / metabolism*
  • Animals
  • Cell Cycle
  • Cell Line
  • Cell Proliferation
  • Cellular Senescence
  • Fibroblasts / metabolism*
  • Genotype
  • HCT116 Cells
  • Humans
  • Kinetics
  • Mice
  • Mice, Mutant Strains
  • Mutation
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Phenotype
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Recombination, Genetic
  • Transfection
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Peptide Fragments
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2