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"=>{"pui"=>"550365951", "sgr"=>"84891713034", "issn"=>"1545-7885", "pmid"=>"19053174", "scopus"=>"2-s2.0-84891713034", "doi"=>"10.1371/journal.pbio.0060301", "isbn"=>"1545-7885 (Electronic)\\r1544-9173 (Linking)"}, "id"=>"07644a82-acfd-308d-a5c0-6b8a9550fd2e", "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"=>"http://www.mendeley.com/research/senescenceassociated-secretory-phenotypes-reveal-cellnonautonomous-functions-oncogenic-ras-p53-tumor", "reader_count"=>792, "reader_count_by_academic_status"=>{"Unspecified"=>28, "Professor > Associate Professor"=>38, "Librarian"=>1, "Student > Doctoral Student"=>45, "Researcher"=>148, "Student > Ph. D. 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  • {"files"=>["https://ndownloader.figshare.com/files/914579"], "description"=>"<div><p>(A) Soluble factors secreted by the indicated normal cell type (epithelial vs. stromal) were detected by antibody arrays and analyzed as described in the text, Materials and Methods, and <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-sd005\" target=\"_blank\">Datasets S5</a>–<a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-sd008\" target=\"_blank\">S8</a>. Normal prostate epithelial cells (PrECs) were induced to senesce by 10 Gy irradiation, and CM from the PRE and SEN cells were analyzed. The SASP of PrECs was compared side by side to the SASP of SEN(XRA) fibroblasts (WI-38, IMR-90, HCA-2, and BJ). The PRE values for each cell type served as the baseline. Signals higher than baseline are displayed in yellow; signals below baseline are displayed in blue. The heat map key (right) indicates log<sub>2</sub>-fold changes from the baseline. <i>p</i>-Values were calculated by the Student <i>t</i>-test, and are given to the right of the heat map. <i>ns</i> = not significant (<i>p</i> > 0.05) and defines non-SASP factors.</p>\n <p>(B) The log<sub>2</sub>-fold changes for all 120 proteins detected by the antibody arrays were plotted for SEN(XRA) PrECs and SEN(XRA) fibroblasts, relative to their PRE baseline. Seventy-nine secreted factors (66%) followed the same regulatory trend (in red). The remaining factors were not coregulated (depicted in blue).</p>\n <p>(C) Soluble factors produced by the indicated normal or transformed prostate epithelial cells were analyzed by antibody arrays and the results displayed as described for <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-g001\" target=\"_blank\">Figure 1</a>A. For each cell strain or cell line, PRE and SEN signals were averaged and used as the baseline. Signals higher than the baseline are shown in yellow; signals below baseline are displayed in blue. An asterisk (*) indicates SASP factors that are conserved between all fibroblasts (<a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-g001\" target=\"_blank\">Figure 1</a>A) and all epithelial cells.</p></div>", "links"=>[], "tags"=>["epithelial"], "article_id"=>585029, "categories"=>["Biotechnology", "Developmental Biology", "Immunology", "Cancer", "Molecular Biology", "Cell Biology", "Evolutionary Biology"], "users"=>["Jean-Philippe Coppé", "Christopher K Patil", "Francis Rodier", "Yu Sun", "Denise P Muñoz", "Joshua Goldstein", "Peter S Nelson", "Pierre-Yves Desprez", "Judith Campisi"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0060301.g002", "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SASP_of_Human_Epithelial_Cells_/585029", "title"=>"SASP of Human Epithelial Cells", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-02 01:23:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/914679"], "description"=>"<div><p>(A) Overall correlation between XRA and mitoxantrone (MIT)-induced SASPs for all three prostate epithelial cancer cell lines (BPH-1, RWPE-1, and PC-3). Correlations for the individual cell lines are given in the table to the right. The senescence inducer (XRA or MIT) is given in parentheses.</p>\n <p>(B–E) Human tumor cells were isolated from biopsies obtained from the same patient before MIT chemotherapy and from prostate tissue following prostatectomy after MIT chemotherapy. Laser captured cells were analyzed by quantitative RT-PCR for the mRNAs encoding the indicated proteins, as described in Materials and Methods and <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-sd017\" target=\"_blank\">Text S1</a>. The results are displayed on a log<sub>10</sub> scale indicating the values before (horizontal or <i>x</i>-axis) compared to after (vertical or <i>y</i>-axis) chemotherapy (top left panel in [B]). Each black dot in (B, C, and D) represents the results obtained from a single patient. The average values for all patients before versus after chemotherapy are indicated by a red dot (B–D); these values are also represented as a heat map in (E).</p>\n <p>(B) Values for mRNAs encoding proteins associated with senescence (p16 and p21) and proliferation (cyclin A, MCM-3, and PCNA).</p>\n <p>(C) Values for mRNAs encoding SASP-associated proteins (IL-6, IL-8, GM-CSF, GRO-α, IGFBP-2, and IL-1β).</p>\n <p>(D) Value for an mRNA encoding a non-SASP–associated protein (IL-2).</p>\n <p>(E) Averages for the values shown in (B–D). Overall <i>p</i>-values, determined by the Student <i>t</i>-test, and number of paired samples (or patients) analyzed for each mRNA are given to the right of the heat map. Signals higher than the prechemotherapy baseline are shown in red; signals below baseline are displayed in green.</p></div>", "links"=>[], "tags"=>["sasp"], "article_id"=>585127, "categories"=>["Biotechnology", "Developmental Biology", "Immunology", "Cancer", "Molecular Biology", "Cell Biology", "Evolutionary Biology"], "users"=>["Jean-Philippe Coppé", "Christopher K Patil", "Francis Rodier", "Yu Sun", "Denise P Muñoz", "Joshua Goldstein", "Peter S Nelson", "Pierre-Yves Desprez", "Judith Campisi"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0060301.g003", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Chemotherapy_Induced_SASP_in_Culture_and_In_Vivo_/585127", "title"=>"Chemotherapy-Induced SASP in Culture and In Vivo", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-02 01:25:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/451592", "https://ndownloader.figshare.com/files/451650", "https://ndownloader.figshare.com/files/451706", "https://ndownloader.figshare.com/files/451741", "https://ndownloader.figshare.com/files/451794", "https://ndownloader.figshare.com/files/451837", "https://ndownloader.figshare.com/files/451867", "https://ndownloader.figshare.com/files/451920", "https://ndownloader.figshare.com/files/451932", "https://ndownloader.figshare.com/files/451947", "https://ndownloader.figshare.com/files/451960", "https://ndownloader.figshare.com/files/452012", "https://ndownloader.figshare.com/files/452025", "https://ndownloader.figshare.com/files/452037", "https://ndownloader.figshare.com/files/452051", "https://ndownloader.figshare.com/files/452098", "https://ndownloader.figshare.com/files/452110", "https://ndownloader.figshare.com/files/452125", "https://ndownloader.figshare.com/files/452136", "https://ndownloader.figshare.com/files/452162", "https://ndownloader.figshare.com/files/452173", "https://ndownloader.figshare.com/files/452184", "https://ndownloader.figshare.com/files/452190", "https://ndownloader.figshare.com/files/452223", "https://ndownloader.figshare.com/files/452232", "https://ndownloader.figshare.com/files/452264"], "description"=>"<div><p>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.</p> </div>", "links"=>[], "tags"=>["senescence-associated", "secretory", "phenotypes", "cell-nonautonomous", "functions", "oncogenic", "ras", "p53", "suppressor"], "article_id"=>149000, "categories"=>["Biotechnology", "Developmental Biology", "Immunology", "Cancer", "Molecular Biology", "Cell Biology", "Evolutionary Biology"], "users"=>["Jean-Philippe Coppé", "Christopher K Patil", "Francis Rodier", "Yu Sun", "Denise P Muñoz", "Joshua Goldstein", "Peter S Nelson", "Pierre-Yves Desprez", "Judith Campisi"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.0060301.sg001", "https://dx.doi.org/10.1371/journal.pbio.0060301.sg002", "https://dx.doi.org/10.1371/journal.pbio.0060301.sg003", "https://dx.doi.org/10.1371/journal.pbio.0060301.sg004", "https://dx.doi.org/10.1371/journal.pbio.0060301.sg005", "https://dx.doi.org/10.1371/journal.pbio.0060301.sg006", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd001", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd002", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd003", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd004", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd005", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd006", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd007", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd008", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd009", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd010", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd011", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd012", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd013", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd014", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd015", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd016", "https://dx.doi.org/10.1371/journal.pbio.0060301.st001", "https://dx.doi.org/10.1371/journal.pbio.0060301.st002", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd017", "https://dx.doi.org/10.1371/journal.pbio.0060301.sd018"], "stats"=>{"downloads"=>35, "page_views"=>68, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Senescence_Associated_Secretory_Phenotypes_Reveal_Cell_Nonautonomous_Functions_of_Oncogenic_RAS_and_the_p53_Tumor_Suppressor/149000", "title"=>"Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2008-12-02 02:30:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/914970"], "description"=>"<div><p>(A) Soluble factors produced by the indicated fibroblasts were analyzed by antibody arrays and displayed as described for <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-g001\" target=\"_blank\">Figure 1</a>A, but in this case, PRE signals were used as the baseline. Therefore, color intensities represent log<sub>2</sub>-fold changes of SEN CM relative to PRE CM from cells of the same genotype under the same culture conditions. We pooled and averaged highly correlated data (see <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-g001\" target=\"_blank\">Figure 1</a>C) from cells originating from a common tissue (WI-38, IMR-90 from embryonic lung; and HCA-2, BJ from neonatal foreskin), and from senescence induced by REP or XRA. Details of the data processing are provided in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-sd009\" target=\"_blank\">Datasets S9</a>–<a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-sd012\" target=\"_blank\">S12</a>. The senescence inducer is given in parentheses. Signals higher than baseline are shown in yellow; signals below baseline are displayed in blue. The numbers on the heat map key (right) indicates log<sub>2</sub>-fold changes from the baseline.</p>\n <p>(B) WI-38 cells induced to senesce by RAS were immunostained for the SASP proteins IL-6 and IL-8, and the senescence marker p16INK4a.</p>\n <p>(C) Correlations between SASPs induced by RAS versus REP or XRA in fibroblasts from embryonic lung (WI-38, IMR-90, left) or neonatal foreskin (HCA-2, right). Correlations for the individual cell strains and senescence inducers are given in the tables below the graphs.</p>\n <p>(D) Shown are the log<sub>2</sub>-fold values for factors that are significantly increased in CM from fibroblasts induced to senesce by RAS compared to fibroblasts induced to senesce by XRA or REP. Green indicates SEN WI-38 and IMR-90 cells induced to senesce by RAS versus XRA. Red indicates SEN WI-38 and IMR-90 induced to senesce by RAS versus REP. Gray indicates HCA2 cells induced to senesce by RAS versus XRA. Blue indicates HCA2 cells induced to senesce by RAS versus REP.</p>\n <p>(E) Shown are the log<sub>2</sub>-fold values for factors that are uniquely and significantly increased in CM from fibroblasts induced to senesce by RAS compared to PRE CM, but not significantly changed in CM from fibroblasts induced to senesce by XRA or REP. The color code is identical to (D).</p>\n <p>(F) Soluble factors from CM produced by the indicated epithelial cells were analyzed by antibody arrays and displayed as described for <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-g001\" target=\"_blank\">Figure 1</a>A, using PRE CM as the baseline. Signals higher than baseline are shown in yellow; signals below baseline are in blue. Asterisks (*) indicate factors conserved between fibroblasts and epithelial cells.</p>\n <p>(G) Correlations between SASPs induced by RAS versus XRA in prostate epithelial cells.</p></div>", "links"=>[], "tags"=>["ras", "amplifies"], "article_id"=>585417, "categories"=>["Biotechnology", "Developmental Biology", "Immunology", "Cancer", "Molecular Biology", "Cell Biology", "Evolutionary Biology"], "users"=>["Jean-Philippe Coppé", "Christopher K Patil", "Francis Rodier", "Yu Sun", "Denise P Muñoz", "Joshua Goldstein", "Peter S Nelson", "Pierre-Yves Desprez", "Judith Campisi"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0060301.g005", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Oncogenic_RAS_Amplifies_the_SASP_/585417", "title"=>"Oncogenic RAS Amplifies the SASP", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-02 01:30:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/914842"], "description"=>"<div><p>(A) T47D and ZR75.1 cells were incubated for 2 d with CM from PRE fibroblasts, or SEN fibroblasts induced by XRA. The cells were photographed under phase contrast, or analyzed for cluster size using an automated Cellomix imager and software. Smaller cluster or clump sizes (pixel<sup>2</sup>) indicate greater scattering. The senescence inducer is given in parentheses. Quadruple asterisks (****) indicate <i>p</i> < 0.001. Error bars indicate the standard deviation around the mean.</p>\n <p>(B) T47D and ZR75.1 cells were incubated with the indicated CM for 3 d and immunostained for the indicated EMT marker proteins. Induction of the mesenchymal marker vimentin by SEN (XRA) CM is shown by the western blot in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-g007\" target=\"_blank\">Figure 7</a>A.</p>\n <p>(C) Epithelial cell invasion was measured using Boyden chambers containing CM alone or CM plus IL-6 and IL-8 recombinant proteins or IL-6 and IL-8 blocking antibodies, as described in Materials and Methods. After 16–24 h, invasion was scored by counting the number of cells on the underside of the membrane. Invasion stimulated by PRE CM was given a value of one, and other conditions were normalized to this value. Invasion was significantly stimulated by recombinant protein and significantly inhibited by antibodies (<i>p</i> < 0.05). Error bars indicate the standard deviation around the mean.</p></div>", "links"=>[], "tags"=>["sasp", "activities"], "article_id"=>585294, "categories"=>["Biotechnology", "Developmental Biology", "Immunology", "Cancer", "Molecular Biology", "Cell Biology", "Evolutionary Biology"], "users"=>["Jean-Philippe Coppé", "Christopher K Patil", "Francis Rodier", "Yu Sun", "Denise P Muñoz", "Joshua Goldstein", "Peter S Nelson", "Pierre-Yves Desprez", "Judith Campisi"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0060301.g004", "stats"=>{"downloads"=>3, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Novel_SASP_Biological_Activities_and_Key_Factors_/585294", "title"=>"Novel SASP Biological Activities and Key Factors", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-02 01:28:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/915229"], "description"=>"<div><p>(A) T47D and ZR75.1 cells were incubated with the indicated CM for 3 d and then analyzed for cell scattering, immunostained for the indicated proteins, and analyzed for vimentin and actin levels by western blotting. Controls for the immunofluorescence from the same individual experiment are shown in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-g004\" target=\"_blank\">Figure 4</a>B. The senescence inducer is given in parentheses. p53 status was either wild type or deficient (GSE). Manipulations are indicated in sequence, separated by >.</p>\n <p>(B) Epithelial cells were incubated with CM from the indicated WI-38 cells and assayed for invasion as described in Materials and Methods and <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-g003\" target=\"_blank\">Figure 3</a>C. Double asterisks (**) indicate <i>p</i> < 0.02. Error bars indicate the standard deviation around the mean.</p>\n <p>(C) Epithelial cells were incubated with CM from the indicated fibroblasts and cell number was determined by cell counting, total protein, or green fluorescent protein (GFP) fluorescence using epithelial cells expressing GFP, as described in [<a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-b080\" target=\"_blank\">80</a>]. A single asterisks (*) indicates <i>p</i> < 0.05. Error bars indicate the standard deviation around the mean.</p>\n <p>(D) Model for the cell-nonautonomous activities of oncogenic RAS and the p53 tumor suppressor protein. Oncogenic and genotoxic stress of sufficient magnitude to cause senescence induce a SASP, whereby cells secrete inflammatory cytokines, chemokines, and growth factors that can alter the tissue microenvironment and stimulate malignant phenotypes in nearby cells. Thus, in addition to their well-known cell-autonomous effects, oncogenes can promote cancer cell-nonautonomously by inducing a SASP. Oncogenic and genotoxic stress also activate p53, which suppresses cancer by cell-autonomous mechanisms (promoting repair, or inducing apoptosis or senescence). In addition, p53 suppresses cancer by the cell-nonautonomous effects of suppressing the intensity of the SASP and its deleterious effects.</p></div>", "links"=>[], "tags"=>["activities", "amplified"], "article_id"=>585679, "categories"=>["Biotechnology", "Developmental Biology", "Immunology", "Cancer", "Molecular Biology", "Cell Biology", "Evolutionary Biology"], "users"=>["Jean-Philippe Coppé", "Christopher K Patil", "Francis Rodier", "Yu Sun", "Denise P Muñoz", "Joshua Goldstein", "Peter S Nelson", "Pierre-Yves Desprez", "Judith Campisi"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0060301.g007", "stats"=>{"downloads"=>2, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Biological_Activities_of_the_Amplified_SASP_/585679", "title"=>"Biological Activities of the Amplified SASP", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-02 01:34:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/915111"], "description"=>"<div><p>(A) CM containing factors secreted by the indicted cells were analyzed by antibody arrays and displayed, using PRE CM as the baseline. We pooled data from cells of the same genotype (p53 wild type or p53 deficient) under the same culture conditions. SEN indicates pooled data from cells originating from the same tissue (WI-38, IMR-90 from embryonic lung; and HCA-2, BJ from neonatal foreskin) and induced to senesce by REP or XRA. Pooling and averaging of highly correlated samples was performed as described for <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-g005\" target=\"_blank\">Figure 5</a>, and details of the data processing are provided in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-sd013\" target=\"_blank\">Datasets S13</a>–<a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-sd016\" target=\"_blank\">S16</a>. The top four rows are the same top four rows in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-g005\" target=\"_blank\">Figure 5</a>A and are included to serve as a visual reference. The senescence inducer is given in parentheses. p53 status is indicated as either wild type (wt) or deficient (d) owing to either GSE22 expression or expression of an shRNA against p53. Manipulations are indicated in sequence, separated by a greater than symbol (>). The heat map key (right) indicates the log<sub>2</sub>-fold changes. Signals higher than the baseline are shown in yellow; signals below baseline are displayed in blue. Comparison between rows is accurately illustrated in (B) and (C) in which each genetically manipulated cell type is compared to its appropriate control baseline.</p>\n <p>(B) Log<sub>2</sub>-fold values for SASP factors that are significantly increased, or significantly and uniquely (as indicated by double asterisks [**]) elevated, in CM from SEN cells made p53 deficient by GSE22, using untreated wild-type SEN values as the baseline. Green indicates WI-38 cells made senescent by XRA, after which p53 was subsequently inactivated by expressing GSE22 using a lentivirus; these cells do not resume proliferation (“unreverted”) upon p53 inactivation (see <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-sg006\" target=\"_blank\">Figure S6</a>). Blue indicates WI-38 in which p16 was inactivated by an shRNA, induced to senesce by XRA, then infected with the GSE22-expressing lentivirus; these cells do revert (REV) after p53 inactivation. Pink indicates HCA2 cells made SEN by XRA, then infected with GSE22 lentivirus; these cells also revert after p53 inactivation.</p>\n <p>(C) Log<sub>2</sub>-fold values for SASP factors that are significantly increased, or significantly and uniquely (as indicated by double asterisks [**]) elevated, in CM from cells made p53-deficient (by GSE22 expression), then induced to senesce by REP, XRA, or RAS. Red indicates WI-38 and IMR90 (averaged) cells expressing GSE22, then induced to senesce by XRA or REP, using cells made SEN by XRA or REP as a baseline. Gray indicates WI-38, IMR-90, and HCA2 (averaged) expressing GSE22, then made senescent by RAS, using SEN by RAS as a baseline.</p>\n <p>(D) WI-38 cells expressing GSE22 were induced to senesce by XRA and then immunostained for the SASP proteins IL-6 and IL-8, the senescence marker p16INK4a, and p53, which accumulates in the presence of GSE22.</p>\n <p>(E) Comparative graphical representation of the secretory profiles of cells made senescent by XRA or REP (dotted line), RAS (black line), p53 inactivation (GSE22) followed by XRA or REP (blue line), or p53 inactivation (GSE22) followed by RAS (red line). The increased slopes (as indicated by the arrow)indicate amplified SASPs.</p>\n <p>(F) Hierarchical cluster analysis of all the cells analyzed in (A), plus the SASP induced by RAS (see <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-g005\" target=\"_blank\">Figure 5</a>). RAS status is indicated as either wild type (wt) or oncogenic (o) owing to expression of Ha-RAS<sup>v12</sup>.</p>\n <p>(G) WI-38 cells with wild-type (wt) or inactive (GSE) p53 were irradiated or induced to express oncogenic RAS (RAS), and CM was collected 4 or 10 d later. Soluble factors were analyzed by antibody arrays and displayed as described in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-g001\" target=\"_blank\">Figure 1</a>D, using PRE CM as the baseline (black column on the left; see also <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-sg005\" target=\"_blank\">Figure S5</a>C for details). Signals higher than baseline are shown in yellow; signals below baseline are in blue. n/a, not applicable.</p>\n <p>(H) Log<sub>2</sub>-fold values for prostate epithelial cell SASP factors that are significantly or uniquely (as indicated by double asterisks [**]) elevated in CM from p53-deficient cancer cells (PC3, BPH1, and RWPE1) that were induced to senesce by XRA, compared to primary p53 wild-type cells (PrECs) that were induced to senesce by XRA.</p></div>", "links"=>[], "tags"=>["restrains"], "article_id"=>585558, "categories"=>["Biotechnology", "Developmental Biology", "Immunology", "Cancer", "Molecular Biology", "Cell Biology", "Evolutionary Biology"], "users"=>["Jean-Philippe Coppé", "Christopher K Patil", "Francis Rodier", "Yu Sun", "Denise P Muñoz", "Joshua Goldstein", "Peter S Nelson", "Pierre-Yves Desprez", "Judith Campisi"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0060301.g006", "stats"=>{"downloads"=>2, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_p53_Restrains_the_SASP_/585558", "title"=>"p53 Restrains the SASP", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-02 01:32:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/914453"], "description"=>"<div><p>(A) Soluble factors secreted by the indicated cells were detected by antibody arrays and analyzed as described in the text, Materials and Methods; <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-sd018\" target=\"_blank\">Text S2</a>; and <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-sd001\" target=\"_blank\">Datasets S1</a>–<a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-sd004\" target=\"_blank\">S4</a>. For each cell strain, the PRE and SEN signals were averaged and used as the baseline. Senescence (SEN) was induced by either repeatedly passaging the cells (REP, replicative exhaustion) or by exposing them to a relatively high dose (10 Gy) of ionizing radiation (XRA, X-irradiation); for simplification, XRA and REP signals were averaged as a single SEN signal (see also <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-g001\" target=\"_blank\">Figure 1</a>C). Signals higher than baseline are displayed in yellow; signals below baseline are displayed in blue. The numbers on the heat map key (right) indicates log<sub>2</sub>-fold changes from the baseline.</p>\n <p>(B) Validation by immunostaining. PRE WI-38 cells were made senescent by REP or XRA, maintained in 10% serum until fixation, and immunostained for the cytokines IL-6 and IL-8 and the senescence marker p16INK4a.</p>\n <p>(C) Correlation between the SASPs of WI-38 cells induced to senescence by XRA or REP, compared to PRE cells, depicted as log<sub>2</sub>-fold changes.</p>\n <p>(D) WI-38 cells were X-irradiated at the indicated doses. CM was collected 2, 4, 7, or 10 d later, and soluble factors were analyzed by antibody arrays. PRE cells and cells irradiated with 0.5 Gy transiently arrested growth, but resumed proliferation 24–48 h after CM collection. Cells irradiated with 10 Gy became senescent, and therefore did proliferate during and beyond the course of the experiment. PRE and SEN (10 d) signals were averaged and used as the baseline. Signals higher than baseline are displayed in yellow; signals below baseline are displayed in blue.</p>\n <p>(E) PRE and SEN cells were analyzed for the indicated mRNAs by quantitative RT-PCR, and normalized to the corresponding PRE values (baselines). The senescence inducers (REP or XRA) are given in parentheses. Signals higher than baselines are shown in red, signals below baselines are displayed in green, and the fold changes in signals are given to the right of the heat map. The results are averages for four cell strains (WI-38, IMR90, HCA-2, and BJ), and the total number of samples for each condition are given below the heat map. An asterisk (*) indicates non-SASP factors (see <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-sg004\" target=\"_blank\">Figure S4</a>).</p>\n <p>(F) Correlation between mRNA and secreted protein levels for SASP (red) and non-SASP (blue) factors (see <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060301#pbio-0060301-sg004\" target=\"_blank\">Figure S4</a>). PRE and SEN values were averaged to create a baseline; all values were expressed as the log<sub>2</sub>-fold change relative to this baseline; PRE versus baseline and SEN versus baseline are shown.</p></div>", "links"=>[], "tags"=>["biotechnology", "cell biology", "developmental biology", "Evolutionary biology", "immunology", "molecular biology", "oncology"], "article_id"=>584888, "categories"=>["Biotechnology", "Developmental Biology", "Immunology", "Cancer", "Molecular Biology", "Cell Biology", "Evolutionary Biology"], "users"=>["Jean-Philippe Coppé", "Christopher K Patil", "Francis Rodier", "Yu Sun", "Denise P Muñoz", "Joshua Goldstein", "Peter S Nelson", "Pierre-Yves Desprez", "Judith Campisi"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0060301.g001", "stats"=>{"downloads"=>4, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SASP_of_Human_Fibroblasts_/584888", "title"=>"SASP of Human Fibroblasts", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-02 01:21:28"}

PMC Usage Stats | Further Information

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Relative Metric

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