p53, Aging, and Cancer

Division Of Basic Sciences - Nci

Investigators

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Abstract

Cellular senescence is induced by DNA damage, oxidative and other stresses and is characterized by cell cycle arrest and the senescence-associated secretory phenotype (SASP). p53 protein regulates multiple aspects of signaling pathways leading to cellular senescence. delta133p53alpha and p53beta isoforms regulate cellular senescence in human epithelial cells, astrocytes, macrophages and CD8+ T cells (Joruiz SM. et al. Cancers (Basel). 12: 2020). The delta133p53alpha mediated cellular reprogramming is our therapeutic strategy for senescence-associated disorders (Beck J. et al., Carcinogenesis. 41: 1017-1029, 2020) including radiation-induced neurodegeneration (Turnquist C. et al., Neuro Oncol. 21: 474-485, 2019), Alzheimer's disease (Ungerleider K. et al., Cell Cycle. 20: 752-764, 2021) and Hutchinson-Gilford progeria syndrome (HGPS). Tumor Microenvironment regulation: delta133p53alpha and tumor exosome-secreted microRNAs are critical regulators of macrophages and CAR-M in the tumor microenvironment (TME). We showed that macrophages are regulated non-cell-autonomously by mutant p53 protein in cancer cells. Colon cancer cells with gain-of-function (GOF) mutant p53 (e.g., R248W and R273H) secrete exosomes enriched for miR-1246, which are taken up by macrophages and reprogram them to an immune-suppressive, cancer-promoting TAM state. These in vitro findings recapitulate the in vivo TME in colon cancer patients, where cancer mutant p53 and exosomal miR-1246 are associated with immune-suppressive signatures, recruitment of immune-suppressive Treg, epithelial-mesenchymal transition, and poor prognosis. We have found that the endogenous expression of delta133p53alpha is downregulated during monocyte-to-macrophage differentiation, especially in M2 macrophages. Therapeutics: delta133p53alpha inhibits astrocytic SASP-mediated neurotoxicity, which is triggered and amplified by synergistic and non-overlapping activities of A-beta and tau. We have found that brain tissues from cancer survivors with radiotherapy-associated cognitive impairment, like those from AD patients, have increased numbers of senescent cells, mainly astrocytes. Irradiation of primary human astrocytes in vitro induced them to become senescent with diminished expression of delta133p53alpha, accumulation of DNA damage, induction of neurotoxic SASP (e.g., IL-6) and repression of neurotrophic factors (e.g., IGF-1). We have shown that overexpression of delta133p53alpha in astrocytes attenuated DNA damage upon irradiation, repressed IL-6 and restored IGF-1, leading to abrogation of neurotoxicity in neuron-astrocyte co-culture. These data suggest a key role for astrocytic delta133p53alpha in the etiology and potential therapy of radiation-induced cognitive impairment.(Ungerleider, Kyra et al., Neuroscience. 498:190-202, 2022) delta133p53alpha is a therapeutic target that can be enhanced to mitigate progeria-associated pathological changes. We have revealed that endogenous delta133p53alpha expression is diminished upon premature induction of senescence in HGPS-derived fibroblasts, and consistently, overexpressed delta133p53alpha abrogates such premature senescence through inhibiting senescence-inducing p53 targets p21WAF1 and miR-34a. Our data also show that delta133p53alpha overexpression does not correct the progerin-induced nuclear defect, but prevents oxidative stress-associated DNA damage and proinflammatory SASP, which are cellular downstream defects characteristic of HGPS. We have shown that the dominant-negative activity of delta133p53alpha preferentially inhibits p53-mediated cellular senescence. In contrast, p53 target genes involved in DNA repair and apoptosis are not or are minimally inhibited by delta133p53alpha, which would ensure prompt repair of DNA damage and elimination of severely damaged cells to prevent oncogenesis. Consistently, we have also shown that overexpression of delta133p53alpha is non-mutagenic and non-oncogenic in human induced pluripotent stem cells, highlighting a contrast to total knockout or knockdown of all p53 activities. The senescence-selective dominant-negative, non-mutagenic and non-oncogenic properties of delta133p53alpha all support its safe application in therapeutic approaches.