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.
Moore
Lynette
L
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Lu
Xiongbin
X
Ghebranious
Nader
N
Tyner
Stuart
S
Donehower
Lawrence A
LA
D021581:Active Transport, Cell Nucleus; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D016922:Cellular Senescence; D005347:Fibroblasts / Q000378:metabolism*; D005838:Genotype; D045325:HCT116 Cells; D006801:Humans; D007700:Kinetics; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011995:Recombination, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D010446:Peptide Fragments; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2