p53, Aging, and Cancer

p53，衰老与癌症

• 批准号: 10702577
• 负责人: Curtis Harris
• 金额: $ 187.35万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702577
• 关键词: Aging; Alzheimer' s Disease; Apoptosis; Astrocytes; Attenuated; Benign; CD8-Positive T-Lymphocytes; Cancer Survivor; Cell Aging; Cell Cycle; Cell Cycle Arrest; Cells; Characteristics; Chromosomal Instability; Coculture Techniques; Colon Carcinoma; DNA Damage; DNA Repair; DNA Repair Gene; Data; Defect; Disease; Dominant Genes; Dominant-Negative Mutation; Double Strand Break Repair; Ensure; Epithelial; Epithelial Cells; Etiology; Fibroblasts; Gene Expression; Generations; Genes; Human; Immune; Impaired cognition; In Vitro; Insulin-Like Growth Factor I; Interleukin-6; Knock-out; Laboratory Study; Longevity; Malignant Neoplasms; Mediating; Mesenchymal; MicroRNAs; Molecular; Mutation; Nerve Degeneration; Neurons; Neurosciences; Nuclear; Oxidative Stress; Pathologic; Patients; Phenotype; Pluripotent Stem Cells; Progeria; Prognosis; Property; Protein Isoforms; Publishing; Radiation; Radiation therapy; Regulation; Regulatory T-Lymphocyte; Reporting; Repression; Role; Signal Pathway; Stress; Syndrome; T-Lymphocyte; TP53 gene; Teratoma; Testing; Therapeutic; brain tissue; cancer cell; carcinogenesis; cell injury; colon cancer patients; exhaustion; exosome; gain of function; human embryonic stem cell; in vivo; induced pluripotent stem cell; irradiation; knock-down; macrophage; monocyte; mutant; neurotoxic; neurotoxicity; neurotrophic factor; non-oncogenic; overexpression; premature; prevent; recruit; senescence; tau Proteins; therapeutic target; tumor; tumor microenvironment; tumorigenesis

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.

细胞衰老是由DNA损伤，氧化和其他应力诱导的，其特征是细胞周期停滞和衰老相关的分泌表型（SASP）。 p53蛋白调节导致细胞衰老的信号通路的多个方面。 Delta133p53Alpha和P53BETA同工型调节人上皮细胞，星形胶质细胞，巨噬细胞和CD8+ T细胞中的细胞衰老（JoruizSM。SM。Cancers（Basel）（Basel）。12：2020）。 Delta133p53Alpha介导的细胞重编程是我们针对衰老相关疾病的治疗策略（Beck J.等人，致癌作用。41：1017-1029，2020），包括辐射诱导的神经变性，NeuroDegeneration，Turnquist C.等，Neuro Oncol。 （Ungerleider K.等人，细胞周期。20：752-764，2021）和Hutchinson-Gilford Progeria综合征（HGPS）。肿瘤微环境调节：Delta133p53Alpha和肿瘤外泌体分泌的microRNA是巨噬细胞的关键调节剂和肿瘤微环境（TME）中的CAR-M。我们表明，巨噬细胞在癌细胞中突变p53蛋白不自主地调节巨噬细胞。具有功能获取（GOF）突变体P53（例如R248W和R273H）的结肠癌细胞分泌富含miR-1246的外泌体，这些外泌体被巨噬细胞占用，并将其重新编程为免疫抑制的癌症，癌症促进癌症的TAM州。这些体外发现概括了结肠癌患者的体内TME，癌症突变体p53和外泌体miR-1246与免疫抑制的特征，免疫抑制性Treg，上皮 - 间质转变和差的预后有关。我们发现，在单核细胞到巨噬细胞分化，尤其是在M2巨噬细胞中，delta133p53alpha的内源性表达被下调。治疗剂：Delta133p53Alpha抑制星形细胞SASP介导的神经毒性，该神经毒性是由A-Beta和Tau的协同和非重叠活性触发和放大的。我们发现，来自放射疗法相关的认知障碍的癌症幸存者的脑组织（如AD患者的认知障碍）的衰老细胞数量增加，主要是星形胶质细胞。原发性人星形胶质细胞在体外的辐射会诱导它们变得衰老，而Delta133p53alpha的表达降低，DNA损伤的积累，诱导神经毒性SASP（例如IL-6）的诱导（例如IL-6）和神经营养因素的抑制作用（例如，IL-6）（例如，IGF，IGF-1）。我们已经表明，星形胶质细胞中的delta133p53alpha过表达在照射时减弱了DNA损伤，抑制IL-6并恢复了IGF-1，从而导致神经元群体养殖中神经毒性的废除。 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.我们已经透露，在过早诱导HGPS衍生的成纤维细胞衰老后，内源性Delta133p53Alpha表达降低，并且始终如一地过表达delta133p53p53alpha消除了通过抑制衰老诱导的p53目标P21WAF1和mir-34a和mir-34A，从而消除了这种过早衰老的衰老。我们的数据还表明，Delta133p53Alpha过表达并不能纠正过程蛋白诱导的核缺损，而是防止氧化应激相关的DNA损伤和促炎SASP，它们是细胞下游缺陷HGPS的特征。我们已经表明，Delta133p53Alpha的显性阴性活性优先抑制p53介导的细胞衰老。相比之下，DELTA133P53Alpha涉及DNA修复和凋亡涉及的p53靶基因并非或最少抑制，这将确保迅速修复DNA损伤并消除严重受损的细胞以防止肿瘤发生。一致地，我们还表明，在人类诱导的多能干细胞中，delta133p53alpha的过表达是非征状和非共同构成的，突显了与所有p53活性的总敲除或敲除形成对比。 Delta133p53Alpha的衰老选择性主导性，非毒素和非康复特性都支持其在治疗方法中的安全应用。