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
Mech. Ageing Dev.
Date: Dec. 07, 2007
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