Buck Institute for Research on Aging, Novato, CA 94945, USA.
Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Campus de Excelencia Internacional Agroalimentario, 14071, Córdoba, Spain.
Aging (Albany NY). 2021 May 25;13(10):13380-13392. doi: 10.18632/aging.203110.
Cellular senescence is a cell fate response characterized by a permanent cell cycle arrest driven primarily the by cell cycle inhibitor and tumor suppressor proteins p16 and p21. In mice, the p21 encoding locus, , is known to generate two transcripts that produce identical proteins, but one of these transcript variants is poorly characterized. We show that the transcript variant 2, but not the better-studied variant 1, is selectively elevated during natural aging across multiple mouse tissues. Importantly, mouse cells induced to senescence in culture by genotoxic stress (ionizing radiation or doxorubicin) upregulated both transcripts, but with different temporal dynamics: variant 1 responded nearly immediately to genotoxic stress, whereas variant 2 increased much more slowly as cells acquired senescent characteristics. Upon treating mice systemically with doxorubicin, which induces widespread cellular senescence , variant 2 increased to a larger extent than variant 1. Variant 2 levels were also more sensitive to the senolytic drug ABT-263 in naturally aged mice. Thus, variant 2 is a novel and more sensitive marker than variant 1 or total p21 protein for assessing the senescent cell burden and clearance in mice.
细胞衰老是一种细胞命运反应，其特征是主要由细胞周期抑制剂和肿瘤抑制蛋白 p16 和 p21 驱动的永久细胞周期停滞。在小鼠中，p21 编码基因座 已知会产生两种产生相同蛋白质的转录本，但其中一种转录本变体的特征描述较差。我们表明，转录本变体 2 而不是研究较多的变体 1，在多种小鼠组织的自然衰老过程中选择性地上调。重要的是，通过遗传毒性应激（电离辐射或阿霉素）在培养物中诱导衰老的小鼠细胞上调了这两种转录本，但具有不同的时间动态：变体 1 几乎立即对遗传毒性应激做出反应，而变体 2 则随着细胞获得衰老特征而增加得更慢。用阿霉素全身性处理小鼠，会诱导广泛的细胞衰老 ，变体 2 的增加幅度大于变体 1。在自然衰老的小鼠中，变体 2 水平对 senolytic 药物 ABT-263 也更敏感。因此，与变体 1 或总 p21 蛋白相比，变体 2 是评估小鼠衰老细胞负担和清除的新型和更敏感的标志物。
