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

Davalos, Albert R.; Kawahara, Misako; Malhotra, Gautam K.; Schaum, Nicholas; Huang, Jiahao; Ved, Urvi; Beausejour, Christian M.; Coppe, Jean-Philippe; Rodier, Francis; Campisi, Judith

doi:10.1083/jcb.201206006

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

Journal Article · Mon May 06 00:00:00 EDT 2013 · Journal of Cell Biology

DOI:https://doi.org/10.1083/jcb.201206006· OSTI ID:1625164

Davalos, Albert R. ^[1]; Kawahara, Misako ^[2]; Malhotra, Gautam K. ^[2]; Schaum, Nicholas ^[3]; Huang, Jiahao ^[2]; Ved, Urvi ^[2]; Beausejour, Christian M. ^[4]; Coppe, Jean-Philippe ^[2]; Rodier, Francis ^[5]; Campisi, Judith ^[5]

Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division; Buck Inst. for Research on Aging, Novato, CA (United States); DOE/OSTI
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division
Buck Inst. for Research on Aging, Novato, CA (United States)
The Centre Hospitalier Univ. (CHU) Ste-Justine, Ste-Justine, Montréal (Canada). Dépt. de Pharmacologie
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division; Buck Inst. for Research on Aging, Novato, CA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC03-76SF00098

OSTI ID:: 1625164

Journal Information:: Journal of Cell Biology, Journal Name: Journal of Cell Biology Journal Issue: 4 Vol. 201; ISSN 0021-9525

Publisher:: Rockefeller University PressCopyright Statement

Country of Publication:: United States

Language:: English

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