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 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.

p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration

“…To examine whether p53 isoforms Δ133p53 and p53β are expressed in the human brain, immunofluorescence staining using Δ133p53-specific antibody MAP4 and p53β-specific antibody TLQ40 30,31 was performed in non-disease human brain tissues (Supplementary Table S1). The specificity of the isoform-specific antibodies in immunofluorescence staining was confirmed using a p53-null cell line H358 with a Δ133p53, full-length p53, or p53β expression vector (Supplementary Figures S1A and B).…”

“…29 Δ133p53, an N-terminal truncated isoform, functions as a negative regulator of cellular senescence by dominant-negatively inhibiting full-length p53. 30,31 p53β, a C-terminal modified isoform, functions as a co-activator of full-length p53 to promote senescence. 30,31 In this study, we report that Δ133p53 and p53β regulate the neuroprotective and neurotoxic functions of human astrocytes.…”

“…30,31 p53β, a C-terminal modified isoform, functions as a co-activator of full-length p53 to promote senescence. 30,31 In this study, we report that Δ133p53 and p53β regulate the neuroprotective and neurotoxic functions of human astrocytes. Using a neuron-astrocyte co-culture system, we demonstrate that downregulation of Δ133p53 or upregulation of p53β in astrocytes promotes SASP and non-cell autonomous neurotoxicity.…”

Cellular senescence impact on immune cell fate and function

“…Mondal et al . (2013) reported that alternative dominant‐negative p53 splicing forms, namely Δ133p53 and p53β, are central players during in vitro and in vivo induced human T‐cell senescence. p53β overexpression or ∆133p53 down‐regulation represses CD28 gene transcription in human cells (Mondal et al ., 2013).…”

“…(2013) reported that alternative dominant‐negative p53 splicing forms, namely Δ133p53 and p53β, are central players during in vitro and in vivo induced human T‐cell senescence. p53β overexpression or ∆133p53 down‐regulation represses CD28 gene transcription in human cells (Mondal et al ., 2013). Accordingly, forced expression of ∆133p53 or CD28 in CD8 + CD28 null human T cells is sufficient to delay telomere‐dependent growth arrest following culture exhaustion, but failed to permanently prevent the process (Parish et al ., 2010).…”