Chemokine receptor CXCR2 is transactivated by p53 and induces p38-mediated cellular senescence in response to DNA damage

Authors

  • Haiyang Guo,

    1. Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China
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  • Zhaojian Liu,

    1. Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China
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  • Bing Xu,

    1. Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China
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  • Huili Hu,

    1. Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China
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  • Zhao Wei,

    1. Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China
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  • Qiao Liu,

    1. Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China
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  • Xiyu Zhang,

    1. Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China
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  • Xuebin Ding,

    1. Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China
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  • Yu Wang,

    1. Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China
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  • Minnan Zhao,

    1. Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China
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  • Yaoqin Gong,

    1. Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China
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  • Changshun Shao

    Corresponding author
    1. Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China
    2. Department of Genetics, Rutgers University, Piscataway, NJ, USA
    • Correspondence

      Changshun Shao, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China. Tel.: +86 531 8838 2043; fax: +86 531 8838 2502; e-mail: shaochangshun@sdu.edu.cn

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Summary

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.

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