p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype

• Published in: The EMBO journal Vol. 30; no. 8; pp. 1536 - 1548
• Main Authors: Freund, Adam, Patil, Christopher K, Campisi, Judith
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 20.04.2011; Nature Publishing Group UK; Springer Nature B.V; Nature Publishing Group
• Subjects: aging; Blotting, Western; cancer; Cells; Cells, Cultured; Cellular Senescence; Chromatin Immunoprecipitation; Cytokines - metabolism; Deoxyribonucleic acid; DNA; DNA Damage; EMBO13; EMBO37; Fibroblasts - metabolism; Fluorescent Antibody Technique; Genotype & phenotype; Growth factors; Humans; inflammation; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB; p38 Mitogen-Activated Protein Kinases - metabolism; Phenotype; Signal Transduction; Tumor Suppressor Protein p53 - metabolism; tumour suppression; tumour suppression; cancer; NF‐κB; aging; inflammation
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1038/emboj.2011.69

Cellular senescence suppresses cancer by forcing potentially oncogenic cells into a permanent cell cycle arrest. Senescent cells also secrete growth factors, proteases, and inflammatory cytokines, termed the senescence‐associated secretory phenotype (SASP). Much is known about pathways that regulate the senescence growth arrest, but far less is known about pathways that regulate the SASP. We previously showed that DNA damage response (DDR) signalling is essential, but not sufficient, for the SASP, which is restrained by p53. Here, we delineate another crucial SASP regulatory pathway and its relationship to the DDR and p53. We show that diverse senescence‐inducing stimuli activate the stress‐inducible kinase p38MAPK in normal human fibroblasts. p38MAPK inhibition markedly reduced the secretion of most SASP factors, constitutive p38MAPK activation was sufficient to induce an SASP, and p53 restrained p38MAPK activation. Further, p38MAPK regulated the SASP independently of the canonical DDR. Mechanistically, p38MAPK induced the SASP largely by increasing NF‐κB transcriptional activity. These findings assign p38MAPK a novel role in SASP regulation—one that is necessary, sufficient, and independent of previously described pathways. Senescent cells were shown to secrete inflammatory cytokines and growth factors, depending upon activation of the DNA damage response. Campisi and colleagues now show that this also requires additional signalling via the stress‐activated p38MAP kinase pathway.