The prosurvival IKK-related kinase IKKϵ integrates LPS and IL17A signaling cascades to promote Wnt-dependent tumor development in the intestine
dc.citation.epage | 2599 | en_US |
dc.citation.issueNumber | 9 | en_US |
dc.citation.spage | 2587 | en_US |
dc.citation.volumeNumber | 76 | en_US |
dc.contributor.author | Göktuna, S. I. | en_US |
dc.contributor.author | Shostak, K. | en_US |
dc.contributor.author | Chau, T.-L. | en_US |
dc.contributor.author | Heukamp, L.C. | en_US |
dc.contributor.author | Hennuy, B. | en_US |
dc.contributor.author | Duong, H.-Q. | en_US |
dc.contributor.author | Ladang, A. | en_US |
dc.contributor.author | Close, P. | en_US |
dc.contributor.author | Klevernic, I. | en_US |
dc.contributor.author | Olivier, F. | en_US |
dc.contributor.author | Florin, A. | en_US |
dc.contributor.author | Ehx, G. | en_US |
dc.contributor.author | Baron, F. | en_US |
dc.contributor.author | Vandereyken, M. | en_US |
dc.contributor.author | Rahmouni, S. | en_US |
dc.contributor.author | Vereecke, L. | en_US |
dc.contributor.author | Loo, G. V. | en_US |
dc.contributor.author | Büttner, R. | en_US |
dc.contributor.author | Greten, F. R. | en_US |
dc.contributor.author | Chariot, A. | en_US |
dc.date.accessioned | 2018-04-12T11:05:06Z | |
dc.date.available | 2018-04-12T11:05:06Z | |
dc.date.issued | 2016-05 | en_US |
dc.department | Department of Molecular Biology and Genetics | en_US |
dc.description.abstract | Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikkϵ in Wnt-driven tumor development. We found that Ikkϵ was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikkϵ in b-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkϵ to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikkϵ was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding proinflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikkϵ-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikkϵ phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikkϵ to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. | en_US |
dc.description.provenance | Made available in DSpace on 2018-04-12T11:05:06Z (GMT). No. of bitstreams: 1 bilkent-research-paper.pdf: 179475 bytes, checksum: ea0bedeb05ac9ccfb983c327e155f0c2 (MD5) Previous issue date: 2016 | en |
dc.identifier.doi | 10.1158/0008-5472.CAN-15-1473 | en_US |
dc.identifier.issn | 0008-5472 | |
dc.identifier.uri | http://hdl.handle.net/11693/37175 | |
dc.language.iso | English | en_US |
dc.publisher | American Association for Cancer Research | en_US |
dc.relation.isversionof | https://doi.org/10.1158/0008-5472.CAN-15-1473 | en_US |
dc.source.title | Cancer Research | en_US |
dc.subject | Beta catenin | en_US |
dc.subject | I kappa B kinase epsilon | en_US |
dc.subject | Immunoglobulin enhancer binding protein | en_US |
dc.subject | Interleukin 17 | en_US |
dc.subject | Lipopolysaccharide | en_US |
dc.subject | Mitogen activated protein kinase 1 | en_US |
dc.subject | Mitogen activated protein kinase 3 | en_US |
dc.subject | Mitogen activated protein kinase kinase 1 | en_US |
dc.subject | Mitogen activated protein kinase kinase 2 | en_US |
dc.subject | Protein kinase B | en_US |
dc.subject | Stress activated protein kinase 1 | en_US |
dc.subject | Wnt protein | en_US |
dc.subject | I kappa B kinase | en_US |
dc.subject | Interleukin 17 | en_US |
dc.subject | Lipopolysaccharide | en_US |
dc.subject | Wnt protein | en_US |
dc.subject | Animal cell | en_US |
dc.subject | Animal experiment | en_US |
dc.subject | Animal model | en_US |
dc.subject | Animal tissue | en_US |
dc.subject | Apoptosis | en_US |
dc.subject | Article | en_US |
dc.subject | Cancer growth | en_US |
dc.subject | Cancer incidence | en_US |
dc.subject | Cancer survival | en_US |
dc.subject | Controlled study | en_US |
dc.subject | Intestine cancer | en_US |
dc.subject | Intestine epithelium cell | en_US |
dc.subject | Mouse | en_US |
dc.subject | Nonhuman | en_US |
dc.subject | Positive feedback | en_US |
dc.subject | Priority journal | en_US |
dc.subject | Protein expression | en_US |
dc.subject | Protein function | en_US |
dc.subject | Protein phosphorylation | en_US |
dc.subject | Signal transduction | en_US |
dc.subject | Tumor associated leukocyte | en_US |
dc.subject | Tumor microenvironment | en_US |
dc.subject | Tumor promotion | en_US |
dc.subject | Animal | en_US |
dc.subject | Disease model | en_US |
dc.subject | Flow cytometry | en_US |
dc.subject | Human | en_US |
dc.subject | Immunoprecipitation | en_US |
dc.subject | In situ hybridization | en_US |
dc.subject | Intestine tumor | en_US |
dc.subject | Metabolism | en_US |
dc.subject | Pathology | en_US |
dc.subject | Physiology | en_US |
dc.subject | Real time polymerase chain reaction | en_US |
dc.subject | Transgenic mouse | en_US |
dc.subject | Tumor cell line | en_US |
dc.subject | Animals | en_US |
dc.subject | Cell Line, Tumor | en_US |
dc.subject | Disease Models, Animal | en_US |
dc.subject | Flow Cytometry | en_US |
dc.subject | Humans | en_US |
dc.subject | I-kappa B Kinase | en_US |
dc.subject | Immunoprecipitation | en_US |
dc.subject | In Situ Hybridization | en_US |
dc.subject | Interleukin-17 | en_US |
dc.subject | Intestinal Neoplasms | en_US |
dc.subject | Lipopolysaccharides | en_US |
dc.subject | Mice | en_US |
dc.subject | Mice, Transgenic | en_US |
dc.subject | Real-Time Polymerase Chain Reaction | en_US |
dc.subject | Signal Transduction | en_US |
dc.subject | Tumor Microenvironment | en_US |
dc.subject | Wnt Proteins | en_US |
dc.title | The prosurvival IKK-related kinase IKKϵ integrates LPS and IL17A signaling cascades to promote Wnt-dependent tumor development in the intestine | en_US |
dc.type | Article | en_US |
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