Tumor Suppressor p53 Functions as a Negative Regulator in IgE-Mediated Mast Cell Activation
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{"title"=>"Tumor suppressor p53 functions as a negative regulator in IgE-mediated mast cell activation", "type"=>"journal", "authors"=>[{"first_name"=>"Kotaro", "last_name"=>"Suzuki", "scopus_author_id"=>"55414275800"}, {"first_name"=>"Samantha H.", "last_name"=>"Murphy", "scopus_author_id"=>"57198933254"}, {"first_name"=>"Yifeng", "last_name"=>"Xia", "scopus_author_id"=>"7403027802"}, {"first_name"=>"Masaya", "last_name"=>"Yokota", "scopus_author_id"=>"43161465500"}, {"first_name"=>"Daiki", "last_name"=>"Nakagomi", "scopus_author_id"=>"37011518200"}, {"first_name"=>"Fei", "last_name"=>"Liu", "scopus_author_id"=>"57096152900"}, {"first_name"=>"Inder M.", "last_name"=>"Verma", "scopus_author_id"=>"7203064176"}, {"first_name"=>"Hiroshi", "last_name"=>"Nakajima", "scopus_author_id"=>"55500098400"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-80053118349", "sgr"=>"80053118349", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0025412", "pui"=>"362619267"}, "id"=>"63abefb3-8bb5-3c95-8ad1-fbea5aaf3048", "abstract"=>"Mast cells are known to play a pivotal role in allergic diseases such as allergic rhinitis, asthma, and atopic dermatitis by releasing granules containing histamine, LTC4, and other preformed chemical mediators. Previous reports have demonstrated that IKK2 (also called IKKβ), a central intracellular component of NF-κB activation pathways, plays a critical role in IgE-mediated degranulation of mast cells and anaphylaxis in mice. In this study, we show that protein levels of tumor suppressor p53 are up-regulated upon IgE-mediated activation in mast cells and lack of p53 results in enhanced responses in both early and late phase anaphylaxis. p53 inhibits not only the catalytic activity of IKK2 presumably through the modulation of glycosylation but also p65 (RelA)-mediated transactivation. Our findings are the first to demonstrate that p53 functions as a negative regulator in mast cells.", "link"=>"http://www.mendeley.com/research/tumor-suppressor-p53-functions-negative-regulator-igemediated-mast-cell-activation-1", "reader_count"=>4, "reader_count_by_academic_status"=>{"Researcher"=>2, "Student > Ph. D. Student"=>1, "Other"=>1}, "reader_count_by_user_role"=>{"Researcher"=>2, "Student > Ph. D. Student"=>1, "Other"=>1}, "reader_count_by_subject_area"=>{"Medicine and Dentistry"=>2, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/732276"], "description"=>"<p>(<b>A</b>) O-GlcNAcylation of IKK2 in WT or p53<sup>−/−</sup> BMMCs was detected by immunoprecipitation with anti-IKK2 antibody, followed by immunoblotting with anti-O-GlcNAc antibody. Shown are representative blots from 5 independent experiments. (<b>B</b>) The expression of TIGAR was assessed by Q-PCR analysis as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025412#pone-0025412-g001\" target=\"_blank\"><b>Figure 1F</b></a>. Data are means ± SD, n = 5, *significantly different from the mean value of controls, *p<0.01. (<b>C</b>) 2-deoxy-D-glucose (2-DG) were given to W/W<sup>v</sup> mice reconstituted with WT or p53<sup>−/−</sup> BMMCs. Twenty hours later, PCA reaction was assessed as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025412#pone-0025412-g002\" target=\"_blank\"><b>Figure 2C</b></a>. Data are means ± SD, n = 6 for each, *p<0.05. (<b>D</b>) WT or p53<sup>−/−</sup> BMMCs were incubated with 2-DG (4.5 mg/ml) for 2 hours. IgE-mediated degranulation was assessed as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025412#pone-0025412-g002\" target=\"_blank\"><b>Figure 2D</b></a>. Data are means ± SD of the percent β-hexosaminidase release, n = 5, *p<0.01. (<b>E</b>) WT BMMCs were incubated with streptozotocin (STZ; 5 mM) or vehicle for 3 hours. O-GlcNAcylation of IKK2 was detected as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025412#pone-0025412-g004\" target=\"_blank\"><b>Figure 4A</b></a>. Shown are representative blots from 5 independent experiments. (<b>F</b>) After incubation with STZ for 3 hours, WT BMMCs were subjected to IgE-mediated degranulation. Data are means ± SD of the percent β-hexosaminidase release, n = 5, *significantly different from the mean value of vehicle, *p<0.05.</p>", "links"=>[], "tags"=>["p53", "mast", "cells", "enhanced", "o-glcnacylation"], "article_id"=>402624, "categories"=>["Molecular Biology", "Biochemistry", "Physiology", "Immunology"], "users"=>["Kotaro Suzuki", "Samantha H. Murphy", "Yifeng Xia", "Masaya Yokota", "Daiki Nakagomi", "Fei Liu", "Inder M. Verma", "Hiroshi Nakajima"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025412.g004", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Lack_of_p53_expression_in_mast_cells_results_in_enhanced_O_GlcNAcylation_of_IKK2_/402624", "title"=>"Lack of p53 expression in mast cells results in enhanced O-GlcNAcylation of IKK2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-23 00:43:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/732371"], "description"=>"<p>(<b>A</b>) W/W<sup>v</sup> mice were reconstituted with WT or p53<sup>−/−</sup> BMMCs and late phase allergic reactions were induced as described in the <b><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025412#s2\" target=\"_blank\">Methods</a></b>. Data were means ± SD of IgE-mediated increase in ear thickness, n = 6 for each genotype, *significantly different from the mean value of WT BMMCs, *p<0.01. (<b>B–E</b>) WT or p53<sup>−/−</sup> BMMCs were stimulated with (black columns) or without (white columns) IgE receptor engagement. (<b>B, C</b>) The levels of TNF-α and IL-6 in the supernatants were quantified by ELISA. Data were means ± SD, n = 5, *significantly different from the mean value of WT BMMCs, *p<0.01. ND = not detected. (<b>D, E</b>) Two hours after IgE receptor engagement, the levels of TNF-α and IL-6 mRNA were quantified by Q-PCR. Data were means ± SD of relative expression, n = 5, *significantly different from the mean value of WT BMMCs, *p<0.05. (<b>F, G</b>) WT or p53<sup>−/−</sup> BMMCs were incubated with ML120B or vehicle for 60 minutes and then stimulated with (black columns) or without (white columns) IgE receptor engagement. Sixty minutes later, the expression of Ifit2 (<b>F</b>) and Ifit3 (<b>G</b>) was assessed by Q-PCR analysis. n = 5, *p<0.01. (<b>H</b>) HEK293 cells were transfected with the expression vectors of IKK2SE, p65, and/or p53 in the presence of NF-κB-luciferase reporter construct. The luciferase activity of NF-κB reporter construct was quantified as described in the <b><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025412#s2\" target=\"_blank\">Methods</a>.</b> Data are means ± SD of the percent luciferase activity, n = 5, *p<0.01.</p>", "links"=>[], "tags"=>["attenuates", "allergic", "reactions", "cytokine"], "article_id"=>402718, "categories"=>["Molecular Biology", "Biochemistry", "Physiology", "Immunology"], "users"=>["Kotaro Suzuki", "Samantha H. Murphy", "Yifeng Xia", "Masaya Yokota", "Daiki Nakagomi", "Fei Liu", "Inder M. Verma", "Hiroshi Nakajima"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025412.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_p53_attenuates_late_phase_allergic_reactions_and_NF_954_B_mediated_cytokine_production_/402718", "title"=>"p53 attenuates late phase allergic reactions and NF-κB-mediated cytokine production.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-23 00:45:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/732189"], "description"=>"<p>(<b>A, B</b>) IgE-mediated SNAP-23 phosphorylation in WT and p53<sup>−/−</sup> BMMCs was analyzed by immunoblotting using phosphorylation site-specific antibody. The representative blots from 4 independent experiments (<b>A</b>) and means ± SD of the density of the blots (<b>B</b>) are shown. *significantly different from the mean value of WT BMMCs, *p<0.01. d.u. = density unit. (<b>C</b>) WT and p53<sup>−/−</sup> BMMCs were incubated with ML120B (10 µM) or vehicle (DMSO (0.01%)). Sixty minutes later, IgE-mediated degranulation was assessed as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025412#pone-0025412-g002\" target=\"_blank\"><b>Figure 2D</b></a>. Data are means ± SD of the percent β-hexosaminidase release, n = 5, *p<0.05. n.s. = not significant.</p>", "links"=>[], "tags"=>["p53", "mast", "cells", "enhanced", "kinase", "ikk2"], "article_id"=>402536, "categories"=>["Molecular Biology", "Biochemistry", "Physiology", "Immunology"], "users"=>["Kotaro Suzuki", "Samantha H. Murphy", "Yifeng Xia", "Masaya Yokota", "Daiki Nakagomi", "Fei Liu", "Inder M. Verma", "Hiroshi Nakajima"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025412.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Lack_of_p53_expression_in_mast_cells_results_in_enhanced_kinase_activity_of_IKK2_and_degranulation_/402536", "title"=>"Lack of p53 expression in mast cells results in enhanced kinase activity of IKK2 and degranulation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-23 00:42:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/369730", "https://ndownloader.figshare.com/files/369743", "https://ndownloader.figshare.com/files/369756", "https://ndownloader.figshare.com/files/369764", "https://ndownloader.figshare.com/files/369780"], "description"=>"<div><p>Mast cells are known to play a pivotal role in allergic diseases such as allergic rhinitis, asthma, and atopic dermatitis by releasing granules containing histamine, LTC4, and other preformed chemical mediators. Previous reports have demonstrated that IKK2 (also called IKKβ), a central intracellular component of NF-κB activation pathways, plays a critical role in IgE-mediated degranulation of mast cells and anaphylaxis in mice. In this study, we show that protein levels of tumor suppressor p53 are up-regulated upon IgE-mediated activation in mast cells and lack of p53 results in enhanced responses in both early and late phase anaphylaxis. p53 inhibits not only the catalytic activity of IKK2 presumably through the modulation of glycosylation but also p65 (RelA)-mediated transactivation. Our findings are the first to demonstrate that p53 functions as a negative regulator in mast cells.</p> </div>", "links"=>[], "tags"=>["suppressor", "p53", "functions", "ige-mediated", "mast", "activation"], "article_id"=>133044, "categories"=>["Molecular Biology", "Biochemistry", "Physiology", "Immunology"], "users"=>["Kotaro Suzuki", "Samantha H. Murphy", "Yifeng Xia", "Masaya Yokota", "Daiki Nakagomi", "Fei Liu", "Inder M. Verma", "Hiroshi Nakajima"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0025412.s001", "https://dx.doi.org/10.1371/journal.pone.0025412.s002", "https://dx.doi.org/10.1371/journal.pone.0025412.s003", "https://dx.doi.org/10.1371/journal.pone.0025412.s004", "https://dx.doi.org/10.1371/journal.pone.0025412.s005"], "stats"=>{"downloads"=>5, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Tumor_Suppressor_p53_Functions_as_a_Negative_Regulator_in_IgE_Mediated_Mast_Cell_Activation/133044", "title"=>"Tumor Suppressor p53 Functions as a Negative Regulator in IgE-Mediated Mast Cell Activation", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-09-23 00:50:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/731974"], "description"=>"<p>(<b>A–B</b>) BMMCs were stimulated with IgE receptor engagement (<b>A</b>) or Nutlin-3a (10 µM) (<b>B</b>) for the indicated times as described in the <b><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025412#s2\" target=\"_blank\">Methods</a></b>. Cells were fixed, permeabilized, incubated with anti-p53-Alexa Fluor 647 (filled histograms) or isotype-matched IgG (dot line), and analyzed by flow cytometry. p53 expression at 24 hours after Nutlin-3a stimulation could not be analyzed because of apoptosis (ND; not determined). Apoptotic cells were assessed by dot plot analysis with Forward/Side Scattering analysis (Gate R1). Shown are representative data from 5 independent experiments. (<b>C</b>) WT BMMCs or p53<sup>−/−</sup> BMMCs were stimulated with IgE receptor engagement as described in the <b><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025412#s2\" target=\"_blank\">Methods</a></b>. Before and 2, 6, and 24 hours after IgE receptor engagement, the expression of p53 and tubulin (as a control) was analyzed by immunoblotting. Shown are representative blots from 4 independent experiments. (<b>D–F</b>) BMMCs were stimulated with (black columns) or without (white columns) either IgE receptor engagement or Nutlin-3a. Four hours later, total RNA was isolated and Q-PCR analysis was performed. The expression of p21<sup>WAF1/CIP1</sup> (<b>D</b>), BAX (<b>E</b>), or TIGAR (<b>F</b>) was normalized to the expression of cyclophylin A. Data are means ± SD of relative expression from 5 independent experiments. *significantly different from the mean value of controls, *p<0.01.</p>", "links"=>[], "tags"=>["p53", "ige-mediated"], "article_id"=>402327, "categories"=>["Molecular Biology", "Biochemistry", "Physiology", "Immunology"], "users"=>["Kotaro Suzuki", "Samantha H. Murphy", "Yifeng Xia", "Masaya Yokota", "Daiki Nakagomi", "Fei Liu", "Inder M. Verma", "Hiroshi Nakajima"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025412.g001", "stats"=>{"downloads"=>3, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Upregulation_of_p53_expression_upon_IgE_mediated_stimulation_/402327", "title"=>"Upregulation of p53 expression upon IgE-mediated stimulation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-23 00:38:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/732082"], "description"=>"<p>(<b>A–C</b>) WT BMMCs or p53<sup>−/−</sup> BMMCs were injected intradermally into the right ear of WBB6F1-W/W<sup>v</sup> mice (W/W<sup>v</sup> mice). Four weeks later, passive cutaneous anaphylaxis (PCA) was induced as described in the <b><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025412#s2\" target=\"_blank\">Methods</a></b>. Ear swelling was quantified before (base line) and 1, 2, 4, and 6 hours after antigen challenge. n = 6 for each group. *significantly different from the mean value of WT BMMCs, *p<0.01. (<b>B</b>) Representative photograph of leakage of injected Evans blue (EB) dye in the ear in W/W<sup>v</sup> mice reconstituted with p53<sup>−/−</sup> BMMCs or WT BMMCs. (<b>C</b>) Quantification of extravasated EB dye in the ear specimens. Data are means ± SD of absorbance at 620 nm, n = 6, each, *p<0.01. (<b>D</b>) WT BMMCs or p53<sup>−/−</sup> BMMCs were stimulated with (black columns) or without (white columns) IgE receptor engagement. Degranulation was assessed by β-hexosaminidase assay. Data are means ± SD of the percent β-hexosaminidase release, n = 6, *p<0.01. (<b>E, F</b>) WT BMMCs or p53<sup>−/−</sup> BMMCs were stimulated with or without IgE receptor engagement for 1 hour. Membrane fusion of BMMCs was assessed by Annexin-V binding by using flow cytometry. Shown are the representative histograms of Annexin-V binding (<b>E</b>) and means ± SD of mean fluorescence intensity (M.F.I.) of Annexin-V binding (<b>F</b>). n = 5, each, *p<0.01.</p>", "links"=>[], "tags"=>["p53", "mast", "cells", "enhanced", "anaphylaxis"], "article_id"=>402431, "categories"=>["Molecular Biology", "Biochemistry", "Physiology", "Immunology"], "users"=>["Kotaro Suzuki", "Samantha H. Murphy", "Yifeng Xia", "Masaya Yokota", "Daiki Nakagomi", "Fei Liu", "Inder M. Verma", "Hiroshi Nakajima"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025412.g002", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Lack_of_p53_expression_in_mast_cells_results_in_enhanced_anaphylaxis_and_degranulation_/402431", "title"=>"Lack of p53 expression in mast cells results in enhanced anaphylaxis and degranulation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-23 00:40:31"}

PMC Usage Stats | Further Information

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