p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes.
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 Δ133p53 and p53β 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 Δ133p53 and increased p53β 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 Δ133p53 protein. In poorly proliferative, Δ133p53-low CD8+CD28- cells, reconstituted expression of either Δ133p53 or CD28 upregulated endogenous expression of each other, which restored cell proliferation, extended replicative lifespan and rescued senescence phenotypes. Conversely, Δ133p53 knockdown or p53β overexpression in CD8+CD28+ cells inhibited cell proliferation and induced senescence. This study establishes a role for Δ133p53 and p53β in regulation of cellular proliferation and senescence in vivo. Furthermore, Δ133p53-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.
Abdul M
AM
Mondal
Izumi
I
Horikawa
Sharon R
SR
Pine
Kaori
K
Fujita
Katherine M
KM
Morgan
Elsa
E
Vera
Sharlyn J
SJ
Mazur
Ettore
E
Appella
Borivoj
B
Vojtesek
Maria A
MA
Blasco
David P
DP
Lane
Curtis C
CC
Harris
D000328:Adult; D000368:Aged; D001343:Autophagy; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D002455:Cell Division; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology*; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000502:physiology; D020033:Protein Isoforms / Q000502:physiology*; D059748:Proteolysis; D011994:Recombinant Proteins / Q000378:metabolism; D014161:Transduction, Genetic; D059016:Tumor Microenvironment; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D055815:Young Adult
D007976:Leupeptins; D018942:Macrolides; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D011994:Recombinant Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C040929:bafilomycin A1; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde