Chemokine receptor CXCR2 is transactivated by p53 and induces p38-mediated cellular senescence in response to DNA damage
Article first published online: 8 SEP 2013
© 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 12, Issue 6, pages 1110–1121, December 2013
How to Cite
Guo, H., Liu, Z., Xu, B., Hu, H., Wei, Z., Liu, Q., Zhang, X., Ding, X., Wang, Y., Zhao, M., Gong, Y. and Shao, C. (2013), Chemokine receptor CXCR2 is transactivated by p53 and induces p38-mediated cellular senescence in response to DNA damage. Aging Cell, 12: 1110–1121. doi: 10.1111/acel.12138
- Issue published online: 21 NOV 2013
- Article first published online: 8 SEP 2013
- Accepted manuscript online: 20 JUL 2013 03:12AM EST
- Manuscript Accepted: 15 JUL 2013
- National Basic Research Program of China. Grant Numbers: 2011CB966200, 2012CB944700
- National Science Foundation Research Grants. Grant Numbers: 81171968, 30771231
- Graduate Student Innovation Fund of Shandong University. Grant Number: 10000080398131
- State Program of National Natural Science Foundation of China for Innovative Research Group. Grant Number: 81021001
- transcriptional activation
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.