Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor
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{"title"=>"Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.", "type"=>"journal", "authors"=>[{"first_name"=>"Jean-Philippe", "last_name"=>"Coppé"}, {"first_name"=>"Christopher K", "last_name"=>"Patil"}, {"first_name"=>"Francis", "last_name"=>"Rodier"}, {"first_name"=>"Yu", "last_name"=>"Sun"}, {"first_name"=>"Denise P", "last_name"=>"Muñoz"}, {"first_name"=>"Joshua", "last_name"=>"Goldstein"}, {"first_name"=>"Peter S", "last_name"=>"Nelson"}, {"first_name"=>"Pierre-Yves", "last_name"=>"Desprez"}, {"first_name"=>"Judith", "last_name"=>"Campisi"}], "year"=>2008, "source"=>"PLoS biology", "identifiers"=>{"doi"=>"10.1371/journal.pbio.0060301", "pui"=>"550365951", "isbn"=>"1545-7885 (Electronic)\\r1544-9173 (Linking)", "scopus"=>"2-s2.0-84891713034", "issn"=>"1545-7885", "pmid"=>"19053174", "sgr"=>"84891713034"}, "keywords"=>["Adult", "Aging", "Antineoplastic Agents", "Antineoplastic Agents: therapeutic use", "Cell Aging", "Cell Aging: physiology", "Cell Line, Tumor", "Cells, Cultured", "Epithelial Cells", "Epithelial Cells: secretion", "Fibroblasts", "Genes, ras", "Genes, ras: physiology", "Humans", "Infant, Newborn", "Interleukin-6", "Interleukin-6: physiology", "Interleukin-8", "Interleukin-8: physiology", "Male", "Neoplasm Invasiveness", "Neoplasm Invasiveness: physiopathology", "Neoplasms", "Neoplasms: etiology", "Phenotype", "Prostatic Neoplasms", "Prostatic Neoplasms: drug therapy", "Prostatic Neoplasms: physiopathology", "Tumor Suppressor Protein p53", "Tumor Suppressor Protein p53: physiology"], "id"=>"ec3eae48-0432-3d10-9400-73d1c5bd3336", "abstract"=>"Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial-mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment.", "link"=>"", "reader_count"=>617, "reader_count_by_academic_status"=>{"Unspecified"=>7, "Professor > Associate Professor"=>31, "Librarian"=>1, "Student > Doctoral Student"=>34, "Researcher"=>128, "Student > Ph. D. 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Student"=>168, "Student > Postgraduate"=>29, "Student > Master"=>88, "Other"=>21, "Student > Bachelor"=>78, "Lecturer"=>6, "Lecturer > Senior Lecturer"=>2, "Professor"=>24}, "reader_count_by_subject_area"=>{"Unspecified"=>14, "Agricultural and Biological Sciences"=>360, "Business, Management and Accounting"=>2, "Chemistry"=>5, "Computer Science"=>2, "Earth and Planetary Sciences"=>1, "Engineering"=>7, "Biochemistry, Genetics and Molecular Biology"=>115, "Nursing and Health Professions"=>1, "Materials Science"=>1, "Medicine and Dentistry"=>85, "Neuroscience"=>6, "Pharmacology, Toxicology and Pharmaceutical Science"=>6, "Physics and Astronomy"=>2, "Social Sciences"=>3, "Immunology and Microbiology"=>7}, "reader_count_by_subdiscipline"=>{"Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>85}, "Social Sciences"=>{"Social Sciences"=>3}, "Physics and Astronomy"=>{"Physics and Astronomy"=>2}, "Unspecified"=>{"Unspecified"=>14}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>6}, "Engineering"=>{"Engineering"=>7}, "Chemistry"=>{"Chemistry"=>5}, "Neuroscience"=>{"Neuroscience"=>6}, "Earth and Planetary Sciences"=>{"Earth and Planetary Sciences"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>7}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>360}, "Computer Science"=>{"Computer Science"=>2}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>2}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>115}}, "reader_count_by_country"=>{"Hungary"=>1, "United States"=>11, "Japan"=>4, "United Kingdom"=>10, "Portugal"=>1, "Spain"=>6, "Russia"=>1, "Greece"=>1, "New Zealand"=>1, "Canada"=>2, "Austria"=>3, "Netherlands"=>1, "Belgium"=>3, "China"=>2, "Finland"=>1, "Brazil"=>1, "Italy"=>3, "France"=>4, "Germany"=>6}, "group_count"=>18}