Aging-associated truncated form of p53 interacts with wild-type p53 and alters p53 stability, localization, and activity.
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.
Mesh Terms:
Active Transport, Cell Nucleus, Aging, Animals, Cell Aging, Cell Cycle, Cell Line, Cell Proliferation, Fibroblasts, Genotype, HCT116 Cells, Humans, Kinetics, Mice, Mice, Mutant Strains, Mutation, Peptide Fragments, Phenotype, Proto-Oncogene Proteins c-mdm2, Recombination, Genetic, Transfection, Tumor Suppressor Protein p53
Active Transport, Cell Nucleus, Aging, Animals, Cell Aging, Cell Cycle, Cell Line, Cell Proliferation, Fibroblasts, Genotype, HCT116 Cells, Humans, Kinetics, Mice, Mice, Mutant Strains, Mutation, Peptide Fragments, Phenotype, Proto-Oncogene Proteins c-mdm2, Recombination, Genetic, Transfection, Tumor Suppressor Protein p53
Mech. Ageing Dev.
Date: Dec. 07, 2007
PubMed ID: 18061646
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