p53, Aging, and Cancer

细胞衰老是由DNA损伤、氧化和其他应激诱导的，其特征是细胞周期阻滞和衰老相关分泌表型（SASP）。P53蛋白调控导致细胞衰老的多个信号通路。delta133p53α和p53β亚型调节人类上皮细胞、星形胶质细胞、巨噬细胞和CD8+ T细胞的细胞衰老。et al。癌症(巴塞尔)。12: 2020)。delta133p53alpha介导的细胞重编程是衰老相关疾病的治疗策略（Beck J. et al., cancer genesis. 41: 1017- 1029,2020），包括辐射诱导的神经变性（Turnquist C. et al., neurooncology . 21: 474-485, 2019），阿尔茨海默病（Ungerleider K. et al., Cell Cycle. 20: 752-764, 2021）和Hutchinson-Gilford早衰综合征（HGPS）。肿瘤微环境调节：delta133p53alpha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到突变p53蛋白的非细胞自主调节。功能获得（GOF）突变p53的结肠癌细胞（如R248W和R273H）分泌富集miR-1246的外泌体，这些外泌体被巨噬细胞摄取并重新编程为免疫抑制，促癌的TAM状态。这些体外研究结果概括了结肠癌患者体内的TME，其中癌症突变体p53和外泌体miR-1246与免疫抑制特征、免疫抑制性Treg的募集、上皮-间质转化和不良预后相关。我们发现，在单核细胞向巨噬细胞分化过程中，内源性delta133p53alpha的表达下调，尤其是在M2巨噬细胞中。治疗方法：delta133p53alpha抑制星形细胞sasp介导的神经毒性，这是由a - β和tau的协同和非重叠活性触发和放大的。我们发现，患有放射治疗相关认知障碍的癌症幸存者的脑组织，如AD患者的脑组织，衰老细胞数量增加，主要是星形胶质细胞。体外辐照原代人星形胶质细胞诱导其衰老，delta133p53alpha表达减少，DNA损伤积累，诱导神经毒性SASP（如IL-6）和神经营养因子（如IGF-1）的抑制。我们已经证明，在星形胶质细胞中过表达delta133p53alpha可减轻辐照后的DNA损伤，抑制IL-6并恢复IGF-1，从而消除神经元-星形胶质细胞共培养中的神经毒性。这些数据表明星形细胞delta133p53alpha在辐射引起的认知障碍的病因和潜在治疗中起关键作用。（Ungerleider, Kyra et al., Neuroscience. 498:190- 202,2022） delta133p53alpha是一种治疗靶点，可以增强以减轻早衰相关的病理变化。我们发现，在hgps来源的成纤维细胞中，内源性delta133p53alpha的表达在过早诱导衰老时减少，并且一致地，过表达的delta133p53alpha通过抑制诱导衰老的p53靶点p21WAF1和miR-34a来消除这种过早衰老。我们的数据还表明，delta133p53alpha过表达不能纠正progerin诱导的核缺陷，但可以防止氧化应激相关的DNA损伤和促炎性SASP，这是HGPS的细胞下游缺陷特征。我们已经证明，delta133p53alpha的显性负活性优先抑制p53介导的细胞衰老。相比之下，p53参与DNA修复和凋亡的靶基因不受delta133p53alpha的抑制，或只受到最低限度的抑制，从而确保DNA损伤的及时修复和严重受损细胞的清除，从而防止肿瘤的发生。一致地，我们还表明，在人类诱导的多能干细胞中，delta133p53alpha的过表达是非致突变性和非致癌性的，突出了与完全敲除或敲除所有p53活性的对比。delta133p53alpha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-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.