Chemokine Signaling via the CXCR2 Receptor Reinforces Senescence

Juan C Acosta, Ana O'Loghlen, Ana Banito, Maria V Guijarro, Arnaud Augert, Selina Raguz, Marzia Fumagalli, Marco Da Costa, Celia Brown, Nikolay Popov, Yoshihiro Takatsu, Jonathan Melamed, Fabrizio d'Adda di Fagagna, David Bernard, Eva Hernando, Jesús Gil

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)1006-1018
Number of pages13
JournalCell
Volume133
Issue number6
DOIs
Publication statusPublished - 13 Jun 2008

Keywords

  • NF-kappa B
  • Animals
  • Chemokines
  • Tumor Suppressor Protein p53
  • Precancerous Conditions
  • DNA Damage
  • Humans
  • Mice
  • CCAAT-Enhancer-Binding Protein-beta
  • Cell Line, Tumor
  • Fibroblasts
  • Down-Regulation
  • Receptors, Interleukin-8A
  • Cell Aging
  • Lung Neoplasms
  • Receptors, Interleukin-8B
  • RNA Interference
  • Adenocarcinoma
  • Signal Transduction
  • Cell Line
  • Ligands

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