Chemokine signaling via the CXCR2 receptor reinforces senescence

被引：1385

作者：

Acosta, Juan C. ^{[1
]}

O'Loghlen, Ana ^{[1
]}

Banito, Ana ^{[1
]}

Guijarro, Maria V. ^{[2
]}

Augert, Arnaud ^{[3
,4
]}

Raguz, Selina ^{[1
]}

Fumagalli, Marzia ^{[5
]}

Da Costa, Marco ^{[1
]}

Brown, Celia ^{[1
]}

Popov, Nikolay ^{[1
]}

Takatsu, Yoshihiro ^{[1
]}

Melamed, Jonathan ^{[2
]}

di Fagagna, Fabrizio d'Adda ^{[5
]}

Bernard, David ^{[3
,4
]}

Hernando, Eva ^{[2
]}

Gil, Jesus ^{[1
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Fac Med, MRC, Clin Sci Ctr,Cell Proliferat Grp, London W12 0NN, England

[2] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA

[3] Univ Lille 1, CNRS, Inst Biol, UMR 8161, Lille, France

[4] Univ Lille 2, Inst Pasteur, IFR 142, Lille, France

[5] Mol Oncol Fdn, IFOM Fdn, FIRC Inst, I-20139 Milan, Italy

来源：

CELL | 2008年 / 133卷 / 06期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1016/j.cell.2008.03.038

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cells enter senescence, a state of stable proliferative arrest, in response to a variety of cellular stresses, including telomere erosion, DNA damage, and oncogenic signaling, which acts as a barrier against malignant transformation in vivo. To identify genes controlling senescence, we conducted an unbiased screen for small hairpin RNAs that extend the life span of primary human fibroblasts. Here, we report that knocking down the chemokine receptor CXCR2 (IL8RB) alleviates both replicative and oncogene-induced senescence (OIS) and diminishes the DNA-damage response. Conversely, ectopic expression of CXCR2 results in premature senescence via a p53-dependent mechanism. Cells undergoing OIS secrete multiple CXCR2-binding chemokines in a program that is regulated by the NF-kappa B and C/EBP beta transcription factors and coordinately induce CXCR2 expression. CXCR2 upregulation is also observed in preneoplastic lesions in vivo. These results suggest that senescent cells activate a self-amplifying secretory network in which CXCR2-binding chemokines reinforce growth arrest.

引用

页码：1006 / 1018

页数：13

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