P53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes.

ABSTRACT: Cellular senescence contributes to aging and decline in tissue function. p53 isoform switching regulates replicative senescence in cultured fibroblasts and is associated with tumor progression. Here, we found that the endogenous p53 isoforms ?133p53 and p53? are physiological regulators of proliferation and senescence in human T lymphocytes in vivo. Peripheral blood CD8+ T lymphocytes collected from healthy donors displayed an age-dependent accumulation of senescent cells (CD28-CD57+) with decreased ?133p53 and increased p53? expression. Human lung tumor-associated CD8+ T lymphocytes also harbored senescent cells. Cultured CD8+ blood T lymphocytes underwent replicative senescence that was associated with loss of CD28 and ?133p53 protein. In poorly proliferative, ?133p53-low CD8+CD28- cells, reconstituted expression of either ?133p53 or CD28 upregulated endogenous expression of each other, which restored cell proliferation, extended replicative lifespan and rescued senescence phenotypes. Conversely, ?133p53 knockdown or p53? overexpression in CD8+CD28+ cells inhibited cell proliferation and induced senescence. This study establishes a role for ?133p53 and p53? in regulation of cellular proliferation and senescence in vivo. Furthermore, ?133p53-induced restoration of cellular replicative potential may lead to a new therapeutic paradigm for treating immunosenescence disorders, including those associated with aging, cancer, autoimmune diseases, and HIV infection.

SUBMITTER: Mondal AM 

PROVIDER: S-EPMC3859419 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature