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

References (90)

HMG domain proteins: architectural elements in the assembly of nucleoprotein structures Grosschedl, Rudolf; Giese, Klaus; Pagel, John Trends in Genetics, Vol. 10, Issue 3 https://doi.org/10.1016/0168-9525(94)90232-1	journal	March 1994
HMGB1, a novel inflammatory cytokine Yamada, Shingo; Maruyama, Ikuro Clinica Chimica Acta, Vol. 375, Issue 1-2 https://doi.org/10.1016/j.cca.2006.07.019	journal	January 2007
Apoptotic Pathways: Ten Minutes to Dead Green, Douglas R. Cell, Vol. 121, Issue 5 https://doi.org/10.1016/j.cell.2005.05.019	journal	June 2005
Senescence of Activated Stellate Cells Limits Liver Fibrosis Krizhanovsky, Valery; Yon, Monica; Dickins, Ross A. Cell, Vol. 135, Issue 1 https://doi.org/10.1016/j.cell.2008.09.015	journal	October 2008
TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain Kawamoto, Tomohiro; Ii, Masayuki; Kitazaki, Tomoyuki European Journal of Pharmacology, Vol. 584, Issue 1 https://doi.org/10.1016/j.ejphar.2008.01.026	journal	April 2008
Inflammatory networks during cellular senescence: causes and consequences Freund, Adam; Orjalo, Arturo V.; Desprez, Pierre-Yves Trends in Molecular Medicine, Vol. 16, Issue 5 https://doi.org/10.1016/j.molmed.2010.03.003	journal	May 2010
Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts Parrinello, Simona; Samper, Enrique; Krtolica, Ana Nature Cell Biology, Vol. 5, Issue 8 https://doi.org/10.1038/ncb1024	journal	July 2003
Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence Kortlever, Roderik M.; Higgins, Paul J.; Bernards, René Nature Cell Biology, Vol. 8, Issue 8 https://doi.org/10.1038/ncb1448	journal	July 2006
Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion Rodier, Francis; Coppé, Jean-Philippe; Patil, Christopher K. Nature Cell Biology, Vol. 11, Issue 8 https://doi.org/10.1038/ncb1909	journal	July 2009
High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal Lotze, Michael T.; Tracey, Kevin J. Nature Reviews Immunology, Vol. 5, Issue 4 https://doi.org/10.1038/nri1594	journal	April 2005
Prostate carcinogenesis: inflammatory storms de Bono, Johann S.; Guo, Christina; Gurel, Bora Nature Reviews Cancer, Vol. 20, Issue 8 https://doi.org/10.1038/s41568-020-0267-9	journal	June 2020
Isolation of genetic suppressor elements, inducing resistance to topoisomerase II-interactive cytotoxic drugs, from human topoisomerase II cDNA. Gudkov, A. V.; Zelnick, C. R.; Kazarov, A. R. Proceedings of the National Academy of Sciences, Vol. 90, Issue 8 https://doi.org/10.1073/pnas.90.8.3231	journal	April 1993
High Mobility Group 1 Protein Is Not Stably Associated with the Chromosomes of Somatic Cells Falciola, Luca; Spada, Fabio; Calogero, Sabina Journal of Cell Biology, Vol. 137, Issue 1 https://doi.org/10.1083/jcb.137.1.19	journal	April 1997
The nuclear protein HMGB1 is secreted by monocytes via a non‐classical, vesicle‐mediated secretory pathway Gardella, Stefania; Andrei, Cristina; Ferrera, Denise EMBO reports, Vol. 3, Issue 10 https://doi.org/10.1093/embo-reports/kvf198	journal	October 2002
Regulated expression and subcellular localization of HMGB1, a chromatin protein with a cytokine function Muller, S.; Ronfani, L.; Bianchi, M. E. Journal of Internal Medicine, Vol. 255, Issue 3 https://doi.org/10.1111/j.1365-2796.2003.01296.x	journal	March 2004
DNA damage response and cellular senescence in tissues of aging mice: Senescent cells in aging mice Wang, Chunfang; Jurk, Diana; Maddick, Mandy Aging Cell, Vol. 8, Issue 3 https://doi.org/10.1111/j.1474-9726.2009.00481.x	journal	May 2009
HMGB1 Is a Therapeutic Target for Sterile Inflammation and Infection Andersson, Ulf; Tracey, Kevin J. Annual Review of Immunology, Vol. 29, Issue 1 https://doi.org/10.1146/annurev-immunol-030409-101323	journal	April 2011
The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression Coppé, Jean-Philippe; Desprez, Pierre-Yves; Krtolica, Ana Annual Review of Pathology: Mechanisms of Disease, Vol. 5, Issue 1 https://doi.org/10.1146/annurev-pathol-121808-102144	journal	January 2010
Masquerader: High Mobility Group Box-1 and Cancer Ellerman, Jessica E.; Brown, Charles K.; de Vera, Michael Clinical Cancer Research, Vol. 13, Issue 10 https://doi.org/10.1158/1078-0432.ccr-06-1953	journal	May 2007
HMGB1 as a DNA-binding cytokine Andersson, Ulf; Erlandsson-Harris, Helena; Yang, Huan Journal of Leukocyte Biology, Vol. 72, Issue 6 https://doi.org/10.1189/jlb.72.6.1084	journal	December 2002
DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion Rodier, F.; Munoz, D. P.; Teachenor, R. Journal of Cell Science, Vol. 124, Issue 1 https://doi.org/10.1242/jcs.071340	journal	November 2010
A Human-Like Senescence-Associated Secretory Phenotype Is Conserved in Mouse Cells Dependent on Physiological Oxygen Coppé, Jean-Philippe; Patil, Christopher K.; Rodier, Francis PLoS ONE, Vol. 5, Issue 2 https://doi.org/10.1371/journal.pone.0009188	journal	February 2010
MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8 Bhaumik, Dipa; Scott, Gary K.; Schokrpur, Shiruyeh Aging, Vol. 1, Issue 4 https://doi.org/10.18632/aging.100042	journal	April 2009
HMGB1: Endogenous Danger Signaling Klune, John R.; Dhupar, Rajeev; Cardinal, Jon Molecular Medicine, Vol. 14, Issue 7-8 https://doi.org/10.2119/2008-00034.klune	journal	April 2008
Loss of ATM Impairs Proliferation of Neural Stem Cells Through Oxidative Stress-Mediated p38 MAPK Signaling Kim, Jeesun; Wong, Paul K. Y. Stem Cells, Vol. 27, Issue 8 https://doi.org/10.1002/stem.125	journal	August 2009
The limited in vitro lifetime of human diploid cell strains Hayflick, L. Experimental Cell Research, Vol. 37, Issue 3 https://doi.org/10.1016/0014-4827(65)90211-9	journal	March 1965
Proinflammatory cytokines (tumor necrosis factor and interleukin 1) stimulate release of high mobility group protein-1 by pituicytes Wang, Haichao; Vishnubhakat, Jaideep M.; Bloom, Ona Surgery, Vol. 126, Issue 2 https://doi.org/10.1016/S0039-6060(99)70182-0	journal	August 1999
Rb-Mediated Heterochromatin Formation and Silencing of E2F Target Genes during Cellular Senescence Narita, Masashi; Nuñez, Sabrina; Heard, Edith Cell, Vol. 113, Issue 6 https://doi.org/10.1016/S0092-8674(03)00401-X	journal	June 2003
Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes Campisi, J. Experimental Gerontology, Vol. 38, Issue 1-2 https://doi.org/10.1016/S0531-5565(02)00152-3	journal	January 2003
Cellular senescence as a tumor-suppressor mechanism Campisi, Judith Trends in Cell Biology, Vol. 11, Issue 11 https://doi.org/10.1016/S0962-8924(01)02151-1	journal	November 2001
High-mobility group box 1 and cancer Tang, Daolin; Kang, Rui; Zeh III, Herbert J. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Vol. 1799, Issue 1-2 https://doi.org/10.1016/j.bbagrm.2009.11.014	journal	January 2010
Cellular senescence in vivo: a barrier to tumorigenesis Prieur, Alexandre; Peeper, Daniel S. Current Opinion in Cell Biology, Vol. 20, Issue 2 https://doi.org/10.1016/j.ceb.2008.01.007	journal	April 2008
A Novel Role for High-Mobility Group A Proteins in Cellular Senescence and Heterochromatin Formation Narita, Masashi; Narita, Masako; Krizhanovsky, Valery Cell, Vol. 126, Issue 3 https://doi.org/10.1016/j.cell.2006.05.052	journal	August 2006
Oncogenic BRAF Induces Senescence and Apoptosis through Pathways Mediated by the Secreted Protein IGFBP7 Wajapeyee, Narendra; Serra, Ryan W.; Zhu, Xiaochun Cell, Vol. 132, Issue 3 https://doi.org/10.1016/j.cell.2007.12.032	journal	February 2008
Chemokine Signaling via the CXCR2 Receptor Reinforces Senescence Acosta, Juan C.; O'Loghlen, Ana; Banito, Ana Cell, Vol. 133, Issue 6 https://doi.org/10.1016/j.cell.2008.03.038	journal	June 2008
Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network Kuilman, Thomas; Michaloglou, Chrysiis; Vredeveld, Liesbeth C. W. Cell, Vol. 133, Issue 6 https://doi.org/10.1016/j.cell.2008.03.039	journal	June 2008
Senescence of Activated Stellate Cells Limits Liver Fibrosis Krizhanovsky, Valery; Yon, Monica; Dickins, Ross A. Cell, Vol. 134, Issue 4 https://doi.org/10.1016/j.cell.2008.06.049	journal	August 2008
HMGB1: guiding immunity from within Dumitriu, Ingrid E.; Baruah, Paramita; Manfredi, Angelo A. Trends in Immunology, Vol. 26, Issue 7 https://doi.org/10.1016/j.it.2005.04.009	journal	July 2005
Cellular senescence as a tumor-suppressor mechanism Campisi, Judith Trends in Cell Biology, Vol. 11 https://doi.org/10.1016/s0962-8924(01)82148-6	journal	November 2001
p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype: p38 regulates the senescence secretory phenotype Freund, Adam; Patil, Christopher K.; Campisi, Judith The EMBO Journal, Vol. 30, Issue 8 https://doi.org/10.1038/emboj.2011.69	journal	March 2011
Release of chromatin protein HMGB1 by necrotic cells triggers inflammation Scaffidi, Paola; Misteli, Tom; Bianchi, Marco E. Nature, Vol. 418, Issue 6894 https://doi.org/10.1038/nature00858	journal	July 2002
Inflammation and cancer Coussens, Lisa M.; Werb, Zena Nature, Vol. 420, Issue 6917 https://doi.org/10.1038/nature01322	journal	December 2002
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas Xue, Wen; Zender, Lars; Miething, Cornelius Nature, Vol. 445, Issue 7128 https://doi.org/10.1038/nature05529	journal	January 2007
Toll-like receptor 9–dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE Tian, Jane; Avalos, Ana Maria; Mao, Su-Yau Nature Immunology, Vol. 8, Issue 5 https://doi.org/10.1038/ni1457	journal	April 2007
Cellular senescence: when bad things happen to good cells Campisi, Judith; d'Adda di Fagagna, Fabrizio Nature Reviews Molecular Cell Biology, Vol. 8, Issue 9 https://doi.org/10.1038/nrm2233	journal	September 2007
Effects on normal fibroblasts and neuroblastoma cells of the activation of the p53 response by the nuclear export inhibitor leptomycin B Smart, Philip; Lane, E. Birgitte; Lane, David P. Oncogene, Vol. 18, Issue 51 https://doi.org/10.1038/sj.onc.1203260	journal	December 1999
Cell surface-bound IL-1 is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network Orjalo, A. V.; Bhaumik, D.; Gengler, B. K. Proceedings of the National Academy of Sciences, Vol. 106, Issue 40 https://doi.org/10.1073/pnas.0905299106	journal	September 2009
A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Dimri, G. P.; Lee, X.; Basile, G. Proceedings of the National Academy of Sciences, Vol. 92, Issue 20 https://doi.org/10.1073/pnas.92.20.9363	journal	September 1995
Use of genetic suppressor elements to dissect distinct biological effects of separate p53 domains. Ossovskaya, V. S.; Mazo, I. A.; Chernov, M. V. Proceedings of the National Academy of Sciences, Vol. 93, Issue 19 https://doi.org/10.1073/pnas.93.19.10309	journal	September 1996
Tumor Suppressor and Aging Biomarker p16INK4a Induces Cellular Senescence without the Associated Inflammatory Secretory Phenotype* Coppé, Jean-Philippe; Rodier, Francis; Patil, Christopher K. Journal of Biological Chemistry, Vol. 286, Issue 42 https://doi.org/10.1074/jbc.M111.257071	journal	October 2011
HMGB1: A signal of necrosis: Review Raucci, Angela; Palumbo, Roberta; Bianchi, Marco E. Autoimmunity, Vol. 40, Issue 4 https://doi.org/10.1080/08916930701356978	journal	January 2007
Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forks Davalos, Albert R.; Campisi, Judith Journal of Cell Biology, Vol. 162, Issue 7 https://doi.org/10.1083/jcb.200304016	journal	September 2003
Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-κB activation Palumbo, Roberta; Galvez, Beatriz G.; Pusterla, Tobias Journal of Cell Biology, Vol. 179, Issue 1 https://doi.org/10.1083/jcb.200704015	journal	October 2007
Four faces of cellular senescence Rodier, Francis; Campisi, Judith The Journal of Cell Biology, Vol. 192, Issue 4 https://doi.org/10.1083/jcb.201009094	journal	February 2011
HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4 Schiraldi, Milena; Raucci, Angela; Muñoz, Laura Martínez Journal of Experimental Medicine, Vol. 209, Issue 3 https://doi.org/10.1084/jem.20111739	journal	February 2012
Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release Venereau, Emilie; Casalgrandi, Maura; Schiraldi, Milena Journal of Experimental Medicine, Vol. 209, Issue 9 https://doi.org/10.1084/jem.20120189	journal	August 2012
Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-κB activation Palumbo, Roberta; Galvez, Beatriz G.; Pusterla, Tobias The Journal of Experimental Medicine, Vol. 204, Issue 11 https://doi.org/10.1084/jem20411oia24	journal	October 2007
Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release Venereau, Emilie; Casalgrandi, Maura; Schiraldi, Milena The Journal of General Physiology, Vol. 140, Issue 4 https://doi.org/10.1085/jgp1404oia6	journal	September 2012
Role of high-mobility group box 1 protein in post-infarction healing process and left ventricular remodelling Kohno, T.; Anzai, T.; Naito, K. Cardiovascular Research, Vol. 81, Issue 3 https://doi.org/10.1093/cvr/cvn291	journal	October 2008
Reversal of human cellular senescence: roles of the p53 and p16 pathways Beausejour, C. M. The EMBO Journal, Vol. 22, Issue 16 https://doi.org/10.1093/emboj/cdg417	journal	August 2003
Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion Bonaldi, T. The EMBO Journal, Vol. 22, Issue 20 https://doi.org/10.1093/emboj/cdg516	journal	October 2003
The acidic C-terminal domain and A-box of HMGB-1 regulates p53-mediated transcription Banerjee, S. Nucleic Acids Research, Vol. 31, Issue 12 https://doi.org/10.1093/nar/gkg412	journal	June 2003
HMGB1 inhibits cell death in yeast and mammalian cells and is abundantly expressed in human breast carcinoma Brezniceanu, Marie-Luise; Völp, Kirsten; Bösser, Susanne The FASEB Journal, Vol. 17, Issue 10 https://doi.org/10.1096/fj.02-0621fje	journal	May 2003
High mobility group protein-1 (HMG-1) is a unique activator of p53 Jayaraman, L.; Moorthy, N. C.; Murthy, K. G. K. Genes & Development, Vol. 12, Issue 4 https://doi.org/10.1101/gad.12.4.462	journal	February 1998
A New Group of Chromatin-Associated Proteins with a High Content of Acidic and Basic Amino Acids Goodwin, Graham H.; Sanders, Clive; Johns, Ernest W. European Journal of Biochemistry, Vol. 38, Issue 1 https://doi.org/10.1111/j.1432-1033.1973.tb03026.x	journal	September 1973
Ionizing radiation-induced long-term expression of senescence markers in mice is independent of p53 and immune status: IR exposure and aging markers Le, Oanh N. L.; Rodier, Francis; Fontaine, Francois Aging Cell, Vol. 9, Issue 3 https://doi.org/10.1111/j.1474-9726.2010.00567.x	journal	March 2010
The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity Lotze, Michael T.; Zeh, Herbert J.; Rubartelli, Anna Immunological Reviews, Vol. 220, Issue 1 https://doi.org/10.1111/j.1600-065X.2007.00579.x	journal	December 2007
Inflammaging as a Major Characteristic of Old People: Can It Be Prevented or Cured? Franceschi, Claudio Nutrition Reviews, Vol. 65 https://doi.org/10.1111/j.1753-4887.2007.tb00358.x	journal	December 2007
Cellular Senescence in Aging Primates Herbig, U. Science, Vol. 311, Issue 5765 https://doi.org/10.1126/science.1122446	journal	March 2006
HMG-1 as a Late Mediator of Endotoxin Lethality in Mice Wang, H. Science, Vol. 285, Issue 5425 https://doi.org/10.1126/science.285.5425.248	journal	July 1999
HMGB1 is secreted by immunostimulated enterocytes and contributes to cytomix-induced hyperpermeability of Caco-2 monolayers Liu, Shiguang; Stolz, Donna B.; Sappington, Penny L. American Journal of Physiology-Cell Physiology, Vol. 290, Issue 4 https://doi.org/10.1152/ajpcell.00308.2005	journal	April 2006
Activation of gene expression in human neutrophils by high mobility group box 1 protein Park, Jong Sung; Arcaroli, John; Yum, Ho-Kee American Journal of Physiology-Cell Physiology, Vol. 284, Issue 4 https://doi.org/10.1152/ajpcell.00322.2002	journal	April 2003
High mobility group box 1 protein interacts with multiple Toll-like receptors Park, Jong Sung; Gamboni-Robertson, Fabia; He, Qianbin American Journal of Physiology-Cell Physiology, Vol. 290, Issue 3 https://doi.org/10.1152/ajpcell.00401.2005	journal	March 2006
The Gene Expression Program of Prostate Fibroblast Senescence Modulates Neoplastic Epithelial Cell Proliferation through Paracrine Mechanisms Bavik, Claes; Coleman, Ilsa; Dean, James P. Cancer Research, Vol. 66, Issue 2 https://doi.org/10.1158/0008-5472.CAN-05-1716	journal	January 2006
Masquerader: High Mobility Group Box-1 and Cancer Ellerman, Jessica E.; Brown, Charles K.; de Vera, Michael Clinical Cancer Research, Vol. 13, Issue 10 https://doi.org/10.1158/1078-0432.CCR-06-1953	journal	May 2007
Tumor Necrosis Factor- α –Induced Secretion of RANTES and Interleukin-6 from Human Airway Smooth-Muscle Cells: Modulation by Cyclic Adenosine Monophosphate Ammit, Alaina J.; Hoffman, Rebecca K.; Amrani, Yassine American Journal of Respiratory Cell and Molecular Biology, Vol. 23, Issue 6 https://doi.org/10.1165/ajrcmb.23.6.4184	journal	December 2000
NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1 Semino, Claudia; Angelini, Giovanna; Poggi, Alessandro Blood, Vol. 106, Issue 2 https://doi.org/10.1182/blood-2004-10-3906	journal	July 2005
A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA Ivanov, Stanimir; Dragoi, Ana-Maria; Wang, Xin Blood, Vol. 110, Issue 6 https://doi.org/10.1182/blood-2006-09-044776	journal	September 2007
DAMPs, PAMPs and alarmins: all we need to know about danger Bianchi, Marco E. Journal of Leukocyte Biology, Vol. 81, Issue 1 https://doi.org/10.1189/jlb.0306164	journal	October 2006
HMGB1 loves company Bianchi, Marco E. Journal of Leukocyte Biology, Vol. 86, Issue 3 https://doi.org/10.1189/jlb.1008585	journal	May 2009
Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation Parrinello, S. Journal of Cell Science, Vol. 118, Issue 3 https://doi.org/10.1242/jcs.01635	journal	January 2005
Stress-induced Premature Senescence (SIPS) Suzuki, Masatoshi; Boothman, David A. Journal of Radiation Research, Vol. 49, Issue 2 https://doi.org/10.1269/jrr.07081	journal	January 2008
Inflammaging as a Major Characteristic of Old People: Can It Be Prevented or Cured? Franceschi, Claudio Nutrition Reviews, Vol. 65, Issue 12 https://doi.org/10.1301/nr.2007.dec.S173-S176	journal	December 2007
Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor Coppé, Jean-Philippe; Patil, Christopher K.; Rodier, Francis PLoS Biology, Vol. 6, Issue 12 https://doi.org/10.1371/journal.pbio.0060301	journal	December 2008
A Versatile Viral System for Expression and Depletion of Proteins in Mammalian Cells Campeau, Eric; Ruhl, Victoria E.; Rodier, Francis PLoS ONE, Vol. 4, Issue 8 https://doi.org/10.1371/journal.pone.0006529	journal	August 2009
HMGB1: Endogenous Danger Signaling Klune, John R.; Dhupar, Rajeev; Cardinal, Jon Molecular Medicine, Vol. 14, Issue 7-8 https://doi.org/10.2119/2008-00034.Klune	journal	April 2008
Redox Modification of Cysteine Residues Regulates the Cytokine Activity of High Mobility Group Box-1 (HMGB1) Yang, Huan; Lundbäck, Peter; Ottosson, Lars Molecular Medicine, Vol. 18, Issue 2 https://doi.org/10.2119/molmed.2011.00389	journal	November 2011
HMGB1 Develops Enhanced Proinflammatory Activity by Binding to Cytokines Sha, Yonggang; Zmijewski, Jaroslaw; Xu, Zhiwei The Journal of Immunology, Vol. 180, Issue 4 https://doi.org/10.4049/jimmunol.180.4.2531	journal	February 2008
Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16 ^ink4a Kosar, Martin; Bartkova, Jirina; Hubackova, Sona Cell Cycle, Vol. 10, Issue 3 https://doi.org/10.4161/cc.10.3.14707	journal	February 2011
Inhibition of p53 by Lentiviral Mediated sh RNA Abrogates G ₁ Arrest and Apoptosis in Retinal Pigmented Epithelial Cell Line Nair, Ayyappan R.; Schliekelman, Mark; Thomas, Mary Beth Cell Cycle, Vol. 4, Issue 5 https://doi.org/10.4161/cc.4.5.1672	journal	March 2005

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Modeling DNA damage-induced pneumopathy in mice: insight from danger signaling cascades Wirsdörfer, Florian; Jendrossek, Verena Radiation Oncology, Vol. 12, Issue 1 https://doi.org/10.1186/s13014-017-0865-1	journal	August 2017
Placental membrane aging and HMGB1 signaling associated with human parturition Menon, Ramkumar; Behnia, Faranak; Polettini, Jossimara Aging, Vol. 8, Issue 2 https://doi.org/10.18632/aging.100891	journal	February 2016
Biomarkers of Cellular Senescence and Skin Aging Wang, Audrey S.; Dreesen, Oliver Frontiers in Genetics, Vol. 9 https://doi.org/10.3389/fgene.2018.00247	journal	August 2018
Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment Cui, Yan; Guo, Gang International Journal of Molecular Sciences, Vol. 17, Issue 11 https://doi.org/10.3390/ijms17111942	journal	November 2016
CMA down-regulates p53 expression through degradation of HMGB1 protein to inhibit irradiation-triggered apoptosis in hepatocellular carcinoma Wu, Jing-Hua; Guo, Jia-Pei; Shi, Jun World Journal of Gastroenterology, Vol. 23, Issue 13 https://doi.org/10.3748/wjg.v23.i13.2308	journal	January 2017
Coordinated control of senescence by lncRNA and a novel T-box3 co-repressor complex Kumar P., Pavan; Emechebe, Uchenna; Smith, Richard eLife, Vol. 3 https://doi.org/10.7554/elife.02805	journal	May 2014
Loss of DNA polymerase β induces cellular senescence: DNA Polymeraseβ Deficiency Drives Senescence Ahmed, Aqila A.; Smoczer, Cristine; Pace, Brianna Environmental and Molecular Mutagenesis, Vol. 59, Issue 7 https://doi.org/10.1002/em.22206	journal	July 2018
Telomere and its role in the aging pathways: telomere shortening, cell senescence and mitochondria dysfunction Zhu, Yukun; Liu, Xuewen; Ding, Xuelu Biogerontology, Vol. 20, Issue 1 https://doi.org/10.1007/s10522-018-9769-1	journal	September 2018
The receptor for advanced glycation end-products (RAGE) is an important pattern recognition receptor (PRR) for inflammaging Teissier, Thibault; Boulanger, Éric Biogerontology, Vol. 20, Issue 3 https://doi.org/10.1007/s10522-019-09808-3	journal	April 2019
Cellular senescence: from growth arrest to immunogenic conversion Burton, D. G. A.; Faragher, R. G. A. AGE, Vol. 37, Issue 2 https://doi.org/10.1007/s11357-015-9764-2	journal	March 2015
Correlations between age, functional status, and the senescence-associated proteins HMGB2 and p16INK4a Lawrence, Ibiyonu; Bene, Michael; Nacarelli, Timothy GeroScience, Vol. 40, Issue 2 https://doi.org/10.1007/s11357-018-0015-1	journal	April 2018
Raman fingerprints as promising markers of cellular senescence and aging Liendl, Lisa; Grillari, Johannes; Schosserer, Markus GeroScience, Vol. 42, Issue 2 https://doi.org/10.1007/s11357-019-00053-7	journal	February 2019
The potential role of necroptosis in inflammaging and aging Royce, Gordon H.; Brown-Borg, Holly M.; Deepa, Sathyaseelan S. GeroScience, Vol. 41, Issue 6 https://doi.org/10.1007/s11357-019-00131-w	journal	November 2019
The role of cellular senescence in diabetes mellitus and osteoporosis: molecular pathways and potential interventions Giovos, Georgios; Yavropoulou, Maria P.; Yovos, John G. Hormones, Vol. 18, Issue 4 https://doi.org/10.1007/s42000-019-00132-6	journal	November 2019
Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment Jeon, Ok Hee; Kim, Chaekyu; Laberge, Remi-Martin Nature Medicine, Vol. 23, Issue 6 https://doi.org/10.1038/nm.4324	journal	April 2017
Inside and out: the activities of senescence in cancer Pérez-Mancera, Pedro A.; Young, Andrew R. J.; Narita, Masashi Nature Reviews Cancer, Vol. 14, Issue 8 https://doi.org/10.1038/nrc3773	journal	July 2014
Impaired immune surveillance accelerates accumulation of senescent cells and aging Ovadya, Yossi; Landsberger, Tomer; Leins, Hanna Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-07825-3	journal	December 2018
The dynamic nature of senescence in cancer Lee, Soyoung; Schmitt, Clemens A. Nature Cell Biology, Vol. 21, Issue 1 https://doi.org/10.1038/s41556-018-0249-2	journal	January 2019
Unmasking senescence: context-dependent effects of SASP in cancer Faget, Douglas V.; Ren, Qihao; Stewart, Sheila A. Nature Reviews Cancer, Vol. 19, Issue 8 https://doi.org/10.1038/s41568-019-0156-2	journal	June 2019
The chemistry of senescence Lozano-Torres, Beatriz; Estepa-Fernández, Alejandra; Rovira, Miguel Nature Reviews Chemistry, Vol. 3, Issue 7 https://doi.org/10.1038/s41570-019-0108-0	journal	June 2019
Astrocyte Support for Oligodendrocyte Differentiation can be Conveyed via Extracellular Vesicles but Diminishes with Age Willis, Cory M.; Nicaise, Alexandra M.; Bongarzone, Ernesto R. Scientific Reports, Vol. 10, Issue 1 https://doi.org/10.1038/s41598-020-57663-x	journal	January 2020
Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis Nicaise, Alexandra M.; Wagstaff, Laura J.; Willis, Cory M. Proceedings of the National Academy of Sciences, Vol. 116, Issue 18 https://doi.org/10.1073/pnas.1818348116	journal	March 2019
The exercise cytokine interleukin-15 rescues slow wound healing in aged mice Wong, Wesley; Crane, Elizabeth D.; Kuo, Yikai Journal of Biological Chemistry, Vol. 294, Issue 52 https://doi.org/10.1074/jbc.RA119.010740	journal	December 2019
Transcriptome analysis of Oncidium petals provides new insights into the initiation of petal senescence Yang, Cui-Ping; Xia, Zhi-Qiang; Hu, Jin The Journal of Horticultural Science and Biotechnology, Vol. 94, Issue 1 https://doi.org/10.1080/14620316.2018.1432297	journal	February 2018
Murine mesenchymal cells that express elevated levels of the CDK inhibitor p16(Ink4a) in vivo are not necessarily senescent Frescas, David; Hall, Brandon M.; Strom, Evguenia Cell Cycle, Vol. 16, Issue 16 https://doi.org/10.1080/15384101.2017.1339850	journal	July 2017
A role for cellular senescence in birth timing Cha, Jeeyeon M.; Aronoff, David M. Cell Cycle, Vol. 16, Issue 21 https://doi.org/10.1080/15384101.2017.1371888	journal	September 2017
DNA damage responses in ageing da Silva, Paulo F. L.; Schumacher, Björn Open Biology, Vol. 9, Issue 11 https://doi.org/10.1098/rsob.190168	journal	November 2019
Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging Ziegler, Dorian V.; Wiley, Christopher D.; Velarde, Michael C. Aging Cell, Vol. 14, Issue 1 https://doi.org/10.1111/acel.12287	journal	November 2014
Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence Wiley, Christopher D.; Flynn, James M.; Morrissey, Christapher Aging Cell, Vol. 16, Issue 5 https://doi.org/10.1111/acel.12632	journal	July 2017
Social stress shortens lifespan in mice Razzoli, Maria; Nyuyki-Dufe, Kewir; Gurney, Allison Aging Cell, Vol. 17, Issue 4 https://doi.org/10.1111/acel.12778	journal	May 2018
The bystander effect contributes to the accumulation of senescent cells in vivo da Silva, Paulo F. L.; Ogrodnik, Mikolaj; Kucheryavenko, Olena Aging Cell, Vol. 18, Issue 1 https://doi.org/10.1111/acel.12848	journal	November 2018
Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin Kim, Dong Eun; Dollé, Martijn E. T.; Vermeij, Wilbert P. Aging Cell, Vol. 19, Issue 3 https://doi.org/10.1111/acel.13072	journal	November 2019
The contribution of oxidative stress to platelet senescence during storage Wang, Li; Xie, Rufeng; Fan, Zhijia Transfusion, Vol. 59, Issue 7 https://doi.org/10.1111/trf.15291	journal	April 2019
Cellular Senescence: Aging, Cancer, and Injury Calcinotto, Arianna; Kohli, Jaskaren; Zagato, Elena Physiological Reviews, Vol. 99, Issue 2 https://doi.org/10.1152/physrev.00020.2018	journal	April 2019
Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives Baker, Darren J.; Petersen, Ronald C. Journal of Clinical Investigation, Vol. 128, Issue 4 https://doi.org/10.1172/jci95145	journal	February 2018
Senescent cells and osteoarthritis: a painful connection Jeon, Ok Hee; David, Nathaniel; Campisi, Judith Journal of Clinical Investigation, Vol. 128, Issue 4 https://doi.org/10.1172/jci95147	journal	April 2018
New perspective on targeting the tumor suppressor p53 pathway in the tumor microenvironment to enhance the efficacy of immunotherapy Guo, Gang; Cui, Yan Journal for Immunotherapy of Cancer, Vol. 3, Issue 1 https://doi.org/10.1186/s40425-015-0053-5	journal	March 2015
A proteomic atlas of senescence-associated secretomes for aging biomarker development Basisty, Nathan; Kale, Abhijit; Jeon, Ok Hee PLOS Biology, Vol. 18, Issue 1 https://doi.org/10.1371/journal.pbio.3000599	journal	January 2020
In Vivo and In Vitro Analysis of Age-Associated Changes and Somatic Cellular Senescence in Renal Epithelial Cells Berkenkamp, Birgit; Susnik, Nathan; Baisantry, Arpita PLoS ONE, Vol. 9, Issue 2 https://doi.org/10.1371/journal.pone.0088071	journal	February 2014
Astrocyte senescence promotes glutamate toxicity in cortical neurons Limbad, Chandani; Oron, Tal Ronnen; Alimirah, Fatouma PLOS ONE, Vol. 15, Issue 1 https://doi.org/10.1371/journal.pone.0227887	journal	January 2020
Cellular Senescence and Lung Function during Aging. Yin and Yang Campisi, Judith Annals of the American Thoracic Society, Vol. 13, Issue Supplement_5 https://doi.org/10.1513/annalsats.201609-703aw	journal	December 2016
Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction Victorelli, Stella; Lagnado, Anthony; Halim, Jessica The EMBO Journal, Vol. 38, Issue 23 https://doi.org/10.15252/embj.2019101982	journal	October 2019
Positive and negative effects of cellular senescence during female reproductive aging and pregnancy Velarde, Michael C.; Menon, Ramkumar Journal of Endocrinology, Vol. 230, Issue 2 https://doi.org/10.1530/joe-16-0018	journal	August 2016
Astrocyte Support for Oligodendrocyte Differentiation can be Conveyed via Extracellular Vesicles but Diminishes with Age Willis, Cory M.; Nicaise, Alexandra M.; Bongarzone, Ernesto R. Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.63622	text	January 2020
A Proteomic Atlas of Senescence-Associated Secretomes for Aging Biomarker Development Basisty, Nathan; Kale, Abhijit; Jeon, Okhee SSRN Electronic Journal https://doi.org/10.2139/ssrn.3380253	journal	January 2019
Systemic HMGB1 Neutralization Prevents Postoperative Neurocognitive Dysfunction in Aged Rats Terrando, Niccolò; Yang, Ting; Wang, Xueqin Frontiers in Immunology, Vol. 7 https://doi.org/10.3389/fimmu.2016.00441	journal	October 2016
Cellular Senescence and the Kidney: Potential Therapeutic Targets and Tools Knoppert, Sebastian N.; Valentijn, Floris A.; Nguyen, Tri Q. Frontiers in Pharmacology, Vol. 10 https://doi.org/10.3389/fphar.2019.00770	journal	July 2019
Oxidative stress-mediated HMGB1 biology Yu, Yan; Tang, Daolin; Kang, Rui Frontiers in Physiology, Vol. 6 https://doi.org/10.3389/fphys.2015.00093	journal	April 2015
Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis Vinatier, Claire; Domínguez, Eduardo; Guicheux, Jerome Frontiers in Physiology, Vol. 9 https://doi.org/10.3389/fphys.2018.00706	journal	June 2018

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