Nakamichi Shinji, Yamada Leo, Roselle Christopher, Horikawa Izumi, June Carl H, Harris Curtis C
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Geroscience. 2025 Aug 6. doi: 10.1007/s11357-025-01819-y.
Δ133p53α is a naturally occurring isoform of the tumor suppressor protein p53. Δ133p53α functions as a physiological dominant-negative inhibitor of the full-length p53 protein (commonly referred to as p53). Δ133p53α preferentially inhibits p53-mediated cellular senescence, while it does not inhibit, or may even promote, p53-mediated DNA repair. Owing to this selective inhibitory activity that preserves genome stability, Δ133p53α represents a promising target for enhancement in the prevention and treatment of diseases associated with increased senescence of normal cells. These diseases include Alzheimer's and other neurodegenerative diseases, premature aging diseases such as Hutchinson-Gilford progeria syndrome (HGPS), and idiopathic pulmonary fibrosis (IPF). Current cell-based therapies, which are limited by increased cellular senescence, may also benefit from Δ133p53α-mediated improvements. As an initial application of Δ133p53α in improving therapeutic cells, we here introduce Δ133p53α-armored chimeric antigen receptor (CAR)-T cells. Based on our previous and ongoing studies using various types of senescent human cells in vitro, we also discuss the importance of further exploring the therapeutic potentials of Δ133p53α, with particular focus on HGPS and IPF. The development of mouse models facilitates in vivo evaluation of the therapeutic effects of Δ133p53α, potentially leading to future clinical applications.
Δ133p53α是肿瘤抑制蛋白p53的一种天然存在的异构体。Δ133p53α作为全长p53蛋白（通常称为p53）的生理性显性负抑制剂发挥作用。Δ133p53α优先抑制p53介导的细胞衰老，而不抑制甚至可能促进p53介导的DNA修复。由于这种保留基因组稳定性的选择性抑制活性，Δ133p53α是增强与正常细胞衰老增加相关疾病预防和治疗的一个有前景的靶点。这些疾病包括阿尔茨海默病和其他神经退行性疾病、早衰性疾病如哈钦森 - 吉尔福德早衰综合征（HGPS）以及特发性肺纤维化（IPF）。目前受细胞衰老增加限制的基于细胞的疗法也可能受益于Δ133p53α介导的改善。作为Δ133p53α在改善治疗性细胞方面的初步应用，我们在此引入Δ133p53α武装的嵌合抗原受体（CAR）-T细胞。基于我们之前及正在进行的使用各种类型衰老人类细胞的体外研究，我们还讨论了进一步探索Δ133p53α治疗潜力的重要性，特别关注HGPS和IPF。小鼠模型的开发有助于对Δ133p53α的治疗效果进行体内评估，有可能引领未来的临床应用。
