p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes

J Cell Biol. 2013 May 13;201(4):613-29. doi: 10.1083/jcb.201206006. Epub 2013 May 6.

Abstract

Cellular senescence irreversibly arrests proliferation in response to potentially oncogenic stress. Senescent cells also secrete inflammatory cytokines such as IL-6, which promote age-associated inflammation and pathology. HMGB1 (high mobility group box 1) modulates gene expression in the nucleus, but certain immune cells secrete HMGB1 as an extracellular Alarmin to signal tissue damage. We show that nuclear HMGB1 relocalized to the extracellular milieu in senescent human and mouse cells in culture and in vivo. In contrast to cytokine secretion, HMGB1 redistribution required the p53 tumor suppressor, but not its activator ATM. Moreover, altered HMGB1 expression induced a p53-dependent senescent growth arrest. Senescent fibroblasts secreted oxidized HMGB1, which stimulated cytokine secretion through TLR-4 signaling. HMGB1 depletion, HMGB1 blocking antibody, or TLR-4 inhibition attenuated senescence-associated IL-6 secretion, and exogenous HMGB1 stimulated NF-κB activity and restored IL-6 secretion to HMGB1-depleted cells. Our findings identify senescence as a novel biological setting in which HMGB1 functions and link HMGB1 redistribution to p53 activity and senescence-associated inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Cellular Senescence
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Cytokines / metabolism
  • DNA-Binding Proteins / metabolism
  • Fibroblasts / metabolism
  • Gene Expression Regulation*
  • HMGB1 Protein / metabolism*
  • Humans
  • Inflammation
  • Interleukin-6 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Toll-Like Receptor 4 / metabolism
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cytokines
  • DNA-Binding Proteins
  • HMGB1 Protein
  • Interleukin-6
  • NF-kappa B
  • TLR4 protein, human
  • TP53 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases