Chemokine signaling via the CXCR2 receptor reinforces senescence.
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-kappaB and C/EBPbeta 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.
Cell Proliferation Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, W12 0NN London, UK.
Juan C
JC
Acosta
Ana
A
O'Loghlen
Ana
A
Banito
Maria V
MV
Guijarro
Arnaud
A
Augert
Selina
S
Raguz
Marzia
M
Fumagalli
Marco
M
Da Costa
Celia
C
Brown
Nikolay
N
Popov
Yoshihiro
Y
Takatsu
Jonathan
J
Melamed
Fabrizio
F
d'Adda di Fagagna
David
D
Bernard
Eva
E
Hernando
Jesús
J
Gil
D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D018925:Chemokines / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011230:Precancerous Conditions / Q000378:metabolism; D034622:RNA Interference; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D022782:CCAAT-Enhancer-Binding Protein-beta; D018925:Chemokines; D008024:Ligands; D016328:NF-kappa B; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53