title: p53 amplifies Toll-like receptor 5 response in human primary and cancer cells through interaction with multiple signal transduction pathways.
abstract: The p53 tumor suppressor regulates transcription of genes associated with diverse cellular functions including apoptosis, growth arrest, DNA repair and differentiation. Recently, we established that p53 can modulate expression of Toll-like receptor (TLR) innate immunity genes but the degree of cross-talk between p53 and TLR pathways remained unclear. Here, using gene expression profiling we characterize the global effect of p53 on the TLR5-mediated transcription in MCF7 cells. We found that combined activation of p53 and TLR5 pathways synergistically increases expression of over 200 genes, mostly associated with immunity and inflammation. The synergy was observed in several human cancer cells and primary lymphocytes. The p53-dependent amplification of transcriptional response to TLR5 activation required expression of NFκB subunit p65 and was mediated by several molecular mechanisms including increased phosphorylation of p38 MAP kinase, PI3K and STAT3 signaling. Additionally, p53 induction increased cytokine expression in response to TNFα, another activator of NFκB and MAP kinase pathways, suggesting a broad interaction between p53 and these signaling pathways. The expression of many synergistically induced genes is elevated in breast cancer patients responsive to chemotherapy. We suggest that p53's capacity to enhance immune response could be exploited to increase antitumor immunity and to improve cancer treatment.
authors.affiliation: Chromosome Stability Group, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Shatz
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Shats
authors.affiliation: Chromosome Stability Group, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Menendez
authors.affiliation: Chromosome Stability Group, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Resnick
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051198:Toll-Like Receptor 5 / Q000276:immunology* / Q000378:metabolism; D059467:Transcriptome / Q000276:immunology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000276:immunology* / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; C495346:TLR5 protein, human; C495901:TP53 protein, human; D051198:Toll-Like Receptor 5; D016159:Tumor Suppressor Protein p53
keywords: Toll-like receptor 5; cancer; inflammation; p53; signal transduction