p53, Aging, and Cancer

细胞衰老是由DNA损伤、氧化等应激引起的，以细胞周期停滞和衰老相关分泌表型(SASP)为特征。P53蛋白调节导致细胞衰老的信号通路的多个方面。Delta133p53pha和p53beta亚型调节人上皮细胞、星形胶质细胞、巨噬细胞和CD8+T细胞的细胞衰老(Joruiz SM.等人的研究。癌症(巴塞尔)。12：2020)。Delta133p53pha介导的细胞重编程是我们对衰老相关疾病的治疗策略(Beck J.等人，癌症发生。41：1017-1029,2020)，包括辐射诱导的神经变性(Turnquist C.et al.，Neuro Oncol.21：474-485,2019)，阿尔茨海默病(Ungerleider K.等人，细胞周期)。20：752-764,2021)和Hutchinson-Gilford早衰症(HGPS)。肿瘤微环境调节：在肿瘤微环境(TME)中，delta133p53pha和肿瘤外体分泌的microRNAs是巨噬细胞和CAR-M的关键调节因子。我们发现巨噬细胞受癌细胞中突变型P53蛋白的非细胞自主调节。具有功能获得(GOF)突变型P53的结肠癌细胞(如R248W和R273H)分泌富含miR-1246的外体，这些外体被巨噬细胞摄取并重新编程为免疫抑制和促癌状态。这些体外发现概括了结肠癌患者体内的TME，其中癌症突变P53和外体miR-1246与免疫抑制信号、免疫抑制Treg的募集、上皮-间充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，Delta133p53pha的内源性表达下调，尤其是在M2巨噬细胞中。治疗：delta133p53pha抑制星形胶质细胞SASP介导的神经毒性，这种毒性是由A？还有陶。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。体外培养的原代人脑星形胶质细胞受到辐射诱导后衰老，表现为delta133p53pha表达减少、DNA损伤累积、神经毒性SASP(如IL-6)的诱导和神经营养因子(如IGF-1)的抑制。我们发现，在星形胶质细胞中过表达delta133p53pha可以减轻辐射引起的DNA损伤，抑制IL-6，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。这些数据表明星形胶质细胞delta133p53pha在放射性认知损害的病因和潜在治疗中起着关键作用。Delta133p53pha是一个治疗靶点，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delta133p53pha的表达在过早诱导衰老时减少，并且一致地，过表达的delta133p53pha通过抑制衰老诱导的p53靶标p21WAF1和miR-34a来消除这种过早衰老。我们的数据还表明，delta133p53pha过表达并不能纠正孕激素诱导的核缺陷，但可以防止氧化应激相关的DNA损伤和促炎性SASP，这是HGPS特有的细胞下游缺陷。我们已经证明，delta133p53pha的显性-负性活性优先抑制P53介导的细胞衰老。相比之下，参与DNA修复和凋亡的p53靶基因不受delta133p53pha的抑制或受到最小程度的抑制，这将确保DNA损伤的迅速修复和严重受损细胞的消除，以防止肿瘤发生。我们还一贯地证明，在人类诱导的多能干细胞中，delta133p53pha的过度表达是非诱变和非致癌的，这与完全敲除或下调所有p53活性形成了鲜明对比。Delta133p53pha的衰老选择性、显性负性、非诱变性和非致瘤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.