Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
Aging Cell. 2013 Dec;12(6):1110-21. doi: 10.1111/acel.12138. Epub 2013 Sep 8.
Mammalian cells may undergo permanent growth arrest/senescence when they incur excessive DNA damage. As a key player during DNA damage response (DDR), p53 transactivates an array of target genes that are involved in various cellular processes including the induction of cellular senescence. Chemokine receptor CXCR2 was previously reported to mediate replicative and oncogene-induced senescence in a DDR and p53-dependent manner. Here, we report that CXCR2 is upregulated in various types of cells in response to genotoxic or oxidative stress. Unexpectedly, we found that the upregulation of CXCR2 depends on the function of p53. Like other p53 target genes such as p21, CXCR2 is transactivated by p53. We identified a p53-binding site in the CXCR2 promoter that responds to changes in p53 functional status. Thus, CXCR2 may act downstream of p53. While the senescence-associated secretory phenotype (SASP) exhibits a kinetics that is distinct from that of CXCR2 expression and does not require p53, it reinforces senescence. We further showed that the cellular senescence caused by CXCR2 upregulation is mediated by p38 activation. Our results thus demonstrate CXCR2 as a critical mediator of cellular senescence downstream of p53 in response to DNA damage.
哺乳动物细胞在遭受过多 DNA 损伤时可能会经历永久性生长停滞/衰老。作为 DNA 损伤反应 (DDR) 中的关键参与者，p53 转录激活一系列靶基因，这些基因参与包括诱导细胞衰老在内的各种细胞过程。趋化因子受体 CXCR2 先前被报道以 DDR 和 p53 依赖的方式介导复制和癌基因诱导的衰老。在这里，我们报告 CXCR2 在各种类型的细胞中响应遗传毒性或氧化应激而上调。出乎意料的是，我们发现 CXCR2 的上调依赖于 p53 的功能。与 p21 等其他 p53 靶基因一样，CXCR2 被 p53 转录激活。我们在 CXCR2 启动子中鉴定了一个 p53 结合位点，该位点响应 p53 功能状态的变化。因此，CXCR2 可能作用于 p53 下游。虽然衰老相关分泌表型 (SASP) 的表现与 CXCR2 表达的动力学不同，并且不依赖于 p53，但它增强了衰老。我们进一步表明，由 CXCR2 上调引起的细胞衰老由 p38 的激活介导。因此，我们的结果表明，CXCR2 是 p53 响应 DNA 损伤后细胞衰老的关键介质。
