p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes


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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 p53ß 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 p53ß 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 p53ß overexpression in CD8+CD28+ cells inhibited cell proliferation and induced senescence. This study establishes a role for ?133p53 and p53ß 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. 

Some notes
-NIH CNIO, Czech republic, Singapore
-Journal of clinical investigation
-corresponding author is Curtis Harris at NIH
-Furthermore, ?133p53-induced restora-
tion 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.
-In vivo accumulation of senescent CD8 +  T lymphocytes during physiological 
aging
-Reduced ?133p53 and elevated p53ß expression in senescent CD8 +  blood T 
lymphocytes in vivo
-Senescence-associated phenotypes and p53 isoform expression profile 
in tumor-associated CD8 +  T lymphocytes
-In vitro replicative senescence of CD8 +  T lymphocytes reproduces CD28 
loss and diminished ?133p53 expression observed in vivo
-Reconstitution of either CD28 or ?133p53 restores cell proliferation, 
extends replicative lifespan, and rescues senescence phenotypes in CD8 + CD28 –  
T lymphocytes
-Knockdown of ?133p53 or overexpression of p53ß induces cellular senes-
cence in CD8 + CD28 +  T lymphocytes.
-q
Since ?133p53 is a natural 
isoform of p53 and is physiologically expressed in normal prolifer-
ative cells at high levels, enhanced expression of ?133p53 may lead 
to a safe method for functional restoration of CD8 +  T lymphocytes 
with minimum concern for malignant transformation
-cell culture
-FACS
-proliferation assay
-immunoblot
-immunohistochemistry
-HT Q-FISH
-lentiviral transduction
-SA-beta-gal assay
-siRNA knockdown
-RT-PCR