title: Chemokine receptor CXCR2 is transactivated by p53 and induces p38-mediated cellular senescence in response to DNA damage.
abstract: 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.
authors.affiliation: Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Guo
authors.forename: Zhaojian
authors.initials: Z
authors.lastname: Liu
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
authors.forename: Huili
authors.initials: H
authors.lastname: Hu
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wei
authors.forename: Qiao
authors.initials: Q
authors.lastname: Liu
authors.forename: Xiyu
authors.initials: X
authors.lastname: Zhang
authors.forename: Xuebin
authors.initials: X
authors.lastname: Ding
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Minnan
authors.initials: M
authors.lastname: Zhao
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000528:radiation effects; D004249:DNA Damage; D004789:Enzyme Activation / Q000528:radiation effects; D020935:MAP Kinase Signaling System / Q000528:radiation effects; D051379:Mice; D008969:Molecular Sequence Data; D010641:Phenotype; D011839:Radiation, Ionizing; D023063:Receptors, Interleukin-8B / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000528:radiation effects; D015533:Transcriptional Activation / Q000235:genetics* / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000528:radiation effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D023063:Receptors, Interleukin-8B; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases
keywords: CXCR2; p38; p53; senescence; transcriptional activation