title: Loss of HuR leads to senescence-like cytokine induction in rodent fibroblasts by activating NF-κB.
abstract: BACKGROUND
  HuR (human antigen R) is a ubiquitously expressed member of the Hu/ELAV family of proteins that is involved in diverse biological processes. HuR has also been shown to play an important role in cell cycle arrest during replicative senescence in both human and mouse cells. Senescent cells not only halt their proliferation, but also activate the secretion of proinflammatory cytokines. A persistent DNA damage response is essential for the senescence-associated secretory phenotype (SASP), and increasing evidence has suggested that the SASP is associated with malignancy.
  
  
  METHODS
  Senescence-associated phenotypes were analyzed in MEFs and other cell line in which HuR expression is inhibited by sh-RNA-mediated knockdown.
  
  
  RESULTS
  RNAi-mediated HuR inhibition resulted in an increase in SASP-related cytokines. The induction of SASP factors did not depend on ARF-p53 pathway-mediated cell cycle arrest, but required NF-κB activity. In the absence of HuR, cells were defective in the DNA-damage response, and single strand DNA breaks accumulated, which may have caused the activation of NF-κB and subsequent cytokine induction.
  
  
  CONCLUSIONS
  In the absence of HuR, cells exhibit multiple senescence-associated phenotypes. Our findings suggest that HuR regulates not only the replicative lifespan, but also the expression of SASP-related cytokines in mouse fibroblasts.
  
  
  CONCLUSIONS
  RNA-binding protein HuR protects cells from undergoing senescence. Senescence-associated phenotypes are accelerated in HuR-deficient cells.
authors.affiliation: Research Institute, National Center for Geriatrics and Gerontology, 35 Gengo, Obu, Aichi 474-8511, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Research Institute, National Center for Geriatrics and Gerontology, 35 Gengo, Obu, Aichi 474-8511, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tsugawa
authors.affiliation: Research Institute, National Center for Geriatrics and Gerontology, 35 Gengo, Obu, Aichi 474-8511, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawagishi
authors.affiliation: Research Institute, National Center for Geriatrics and Gerontology, 35 Gengo, Obu, Aichi 474-8511, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Asai
authors.affiliation: Research Institute, National Center for Geriatrics and Gerontology, 35 Gengo, Obu, Aichi 474-8511, Japan. Electronic address: msugimot@ncgg.go.jp.
authors.forename: Masataka
authors.initials: M
authors.lastname: Sugimoto
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016922:Cellular Senescence / Q000502:physiology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D051959:ELAV Proteins; D016328:NF-kappa B; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D020727:ADP-Ribosylation Factors
keywords: HuR; NF-κB; SASP; Senescence