p53, Aging, and Cancer

细胞衰老是由DNA损伤、氧化和其他应激诱导的，其特征在于细胞周期停滞和衰老相关分泌表型（SASP）。p53蛋白调节导致细胞衰老的信号通路的多个方面。δ 133 p53 α和p53 β同种型调节人上皮细胞、星形胶质细胞、巨噬细胞和CD 8 + T细胞中的细胞衰老（Joruiz SM.等人。癌症（巴塞尔）。12：2020）。delta 133 p53 α介导的细胞重编程是我们用于衰老相关病症的治疗策略（Beck J.致癌作用。41：1017-1029，2020），包括辐射诱导的神经变性（Turnquist C.例如，神经肿瘤学21：474-485，2019）、阿尔茨海默病（Ungerleider K.例如，细胞周期20：752-764，2021）和Hutchinson-Gilford早衰综合征（HGPS）。肿瘤微环境调控：delta 133 p53 α和肿瘤外泌体分泌的microRNA是肿瘤微环境（TME）中巨噬细胞和CAR-M的关键调节因子。我们发现巨噬细胞在癌细胞中受突变型p53蛋白的非细胞自主调节。具有功能获得性（GOF）突变p53的结肠癌细胞（例如，R248 W和R273 H）分泌富含miR-1246的外泌体，其被巨噬细胞摄取并将其重编程为免疫抑制、癌症促进的TAM状态。这些体外发现概括了结肠癌患者的体内TME，其中癌症突变体p53和外来体miR-1246与免疫抑制特征、免疫抑制性Treg的募集、上皮-间充质转化和不良预后相关。我们已经发现，在单核细胞向巨噬细胞分化过程中，特别是在M2巨噬细胞中，delta 133 p53 α的内源性表达下调。治疗：delta 133 p53 α抑制星形胶质细胞SASP介导的神经毒性，这是触发和放大的协同和非重叠活动的A？和tau。我们发现，与AD患者一样，患有放射治疗相关认知障碍的癌症幸存者的脑组织中衰老细胞的数量增加，主要是星形胶质细胞。体外照射原代人星形胶质细胞诱导其衰老，delta 133 p53 α表达减少，DNA损伤积累，神经毒性SASP（例如，IL-6）和神经营养因子（例如，IGF-1）。我们已经表明，星形胶质细胞中delta 133 p53 α的过表达减弱了辐射后的DNA损伤，抑制了IL-6并恢复了IGF-1，导致神经元-星形胶质细胞共培养中神经毒性的消除。这些数据表明星形胶质细胞δ 133 p53 α在放射性认知障碍的病因学和潜在治疗中起关键作用。δ 133 p53 α是一种治疗靶点，可以增强其作用以减轻与早老症相关的病理变化。我们已经发现，内源性delta 133 p53 α的表达在HGPS衍生的成纤维细胞中过早诱导衰老时减少，并且一致地，过表达的delta 133 p53 α通过抑制衰老诱导p53靶点p21 WAF 1和miR-34 a来消除这种过早衰老。我们的数据还表明，delta 133 p53 α过表达不能纠正早老蛋白诱导的核缺陷，但可以防止氧化应激相关的DNA损伤和促炎SASP，这是HGPS的细胞下游缺陷特征。我们已经表明，显性负活性delta 133 p53 α优先抑制p53介导的细胞衰老。相反，参与DNA修复和细胞凋亡的p53靶基因不被delta 133 p53 α抑制或受到最低程度的抑制，这将确保DNA损伤的迅速修复和严重损伤细胞的消除以防止肿瘤发生。一致地，我们还表明，delta 133 p53 α的过表达在人诱导多能干细胞中是非致突变性和非致癌性的，突出了与全部p53活性的完全敲除或敲低的对比。delta 133 p53 α的衰老选择性显性阴性、非致突变性和非致癌性都支持其在治疗方法中的安全应用。

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? 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. 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.