TPL2 kinase is a suppressor of lung carcinogenesis

Lung cancer is a heterogeneous disease at both clinical and molecular levels, posing conceptual and practical bottlenecks in defining key pathways affecting its initiation and progression. Molecules with a central role in lung carcinogenesis are likely to be targeted by multiple deregulated pathways and may have prognostic, predictive, and/or therapeutic value. Here, we report that Tumor Progression Locus 2 (TPL2), a kinase implicated in the regulation of innate and adaptive immune responses, fulfils a role as a suppressor of lung carcinogenesis and is subject to diverse genetic and epigenetic aberrations in lung cancer patients. We show that allelic imbalance at the TPL2 locus, up-regulation of microRNA-370, which targets TPL2 transcripts, and activated RAS (rat sarcoma) signaling may result in down-regulation of TPL2 expression. Low TPL2 levels correlate with reduced lung cancer patient survival and accelerated onset and multiplicity of urethane-induced lung tumors in mice. Mechanistically, TPL2 was found to antagonize oncogene-induced cell transformation and survival through a pathway involving p53 downstream of cJun N-terminal kinase (JNK) and be required for optimal p53 response to genotoxic stress. These results identify multiple oncogenic pathways leading to TPL2 deregulation and highlight its major tumor-suppressing function in the lung.

[1]  T. Liloglou,et al.  DNA methylation biomarkers offer improved diagnostic efficiency in lung cancer. , 2012, Cancer research.

[2]  Steven J. M. Jones,et al.  Comprehensive genomic characterization of squamous cell lung cancers , 2012, Nature.

[3]  A. Eliopoulos,et al.  Tpl2 ablation promotes intestinal inflammation and tumorigenesis in Apcmin mice by inhibiting IL-10 secretion and regulatory T-cell generation , 2012, Proceedings of the National Academy of Sciences.

[4]  A. Eliopoulos,et al.  Tpl2 kinase signal transduction in inflammation and cancer. , 2011, Cancer letters.

[5]  M. Barbacid,et al.  c-Raf, but not B-Raf, is essential for development of K-Ras oncogene-driven non-small cell lung carcinoma. , 2011, Cancer cell.

[6]  M. Serrano,et al.  Nature Genetics Advance Online Publication the Stress Kinase Mkk7 Couples Oncogenic Stress to P53 Stability and Tumor Suppression , 2022 .

[7]  T. Liloglou,et al.  UHRF1‐mediated tumor suppressor gene inactivation in nonsmall cell lung cancer , 2011, Cancer.

[8]  Jonathan Chernoff,et al.  Faculty Opinions recommendation of COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. , 2011 .

[9]  G. Watanabe,et al.  Long Interspersed Nuclear Element 1 Hypomethylation Is a Marker of Poor Prognosis in Stage IA Non–Small Cell Lung Cancer , 2010, Clinical Cancer Research.

[10]  J. O’Shea,et al.  Ablation of Tumor Progression Locus 2 Promotes a Type 2 Th Cell Response in Ovalbumin-Immunized Mice , 2009, The Journal of Immunology.

[11]  D. Feldser,et al.  Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma , 2009, Nature.

[12]  A. Levine,et al.  The first 30 years of p53: growing ever more complex , 2009, Nature Reviews Cancer.

[13]  Ben S. Wittner,et al.  Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 , 2009, Nature.

[14]  Patricia Greninger,et al.  A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. , 2009, Cancer cell.

[15]  A. Sher,et al.  Tpl2 kinase regulates T cell interferon-γ production and host resistance to Toxoplasma gondii , 2008, The Journal of experimental medicine.

[16]  Allan Balmain,et al.  Kras regulatory elements and exon 4A determine mutation specificity in lung cancer , 2008, Nature Genetics.

[17]  S. Lippman,et al.  Lung cancer. , 2008, The New England journal of medicine.

[18]  P. Tsichlis,et al.  Proteinase-activated receptor-1-triggered activation of tumor progression locus-2 promotes actin cytoskeleton reorganization and cell migration. , 2008, Cancer research.

[19]  Steven Piantadosi,et al.  DNA methylation markers and early recurrence in stage I lung cancer. , 2008, The New England journal of medicine.

[20]  P. Tsichlis,et al.  Tpl2 and ERK transduce antiproliferative T cell receptor signals and inhibit transformation of chronically stimulated T cells , 2008, Proceedings of the National Academy of Sciences.

[21]  T. Patel,et al.  Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes , 2008, Oncogene.

[22]  B. Fingleton,et al.  Epithelial NF-κB activation promotes urethane-induced lung carcinogenesis , 2007, Proceedings of the National Academy of Sciences.

[23]  Charles D. Johnson,et al.  Genome-scale microRNA and small interfering RNA screens identify small RNA modulators of TRAIL-induced apoptosis pathway. , 2007, Cancer research.

[24]  Pier Paolo Pandolfi,et al.  Nucleophosmin and cancer , 2006, Nature Reviews Cancer.

[25]  R. Stephens,et al.  Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. , 2006, Cancer cell.

[26]  Steve Gerondakis,et al.  Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Jeonghee Cho,et al.  Tpl2/Cot Signals Activate ERK, JNK, and NF-κB in a Cell-type and Stimulus-specific Manner* , 2005, Journal of Biological Chemistry.

[28]  A. Berns,et al.  Mouse models for human lung cancer. , 2005, Genes & development.

[29]  Apiwat Mutirangura,et al.  Distinctive pattern of LINE-1 methylation level in normal tissues and the association with carcinogenesis , 2004, Oncogene.

[30]  Leena Latonen,et al.  Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. , 2004, Cancer cell.

[31]  R. Cardiff,et al.  Classification of Proliferative Pulmonary Lesions of the Mouse , 2004, Cancer Research.

[32]  C. Dumitru,et al.  Tpl2 transduces CD40 and TNF signals that activate ERK and regulates IgE induction by CD40 , 2003, The EMBO journal.

[33]  Y. Miller,et al.  Induction of a high incidence of lung tumors in C57BL/6 mice with multiple ethyl carbamate injections. , 2003, Cancer letters.

[34]  S. Smerdon,et al.  NF-κB1 p105 Negatively Regulates TPL-2 MEK Kinase Activity , 2003, Molecular and Cellular Biology.

[35]  Shao-Cong Sun,et al.  NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase. , 2003, Molecular cell.

[36]  G. Kollias,et al.  Genetic Dissection of the Cellular Pathways and Signaling Mechanisms in Modeled Tumor Necrosis Factor–induced Crohn's-like Inflammatory Bowel Disease , 2002, The Journal of experimental medicine.

[37]  Jeonghee Cho,et al.  Induction of COX‐2 by LPS in macrophages is regulated by Tpl2‐dependent CREB activation signals , 2002, The EMBO journal.

[38]  Pier Giuseppe Pelicci,et al.  Nucleophosmin regulates the stability and transcriptional activity of p53 , 2002, Nature Cell Biology.

[39]  L. Young,et al.  The Oncogenic Protein Kinase Tpl-2/Cot Contributes to Epstein-Barr Virus-Encoded Latent Infection Membrane Protein 1-Induced NF-κB Signaling Downstream of TRAF2 , 2002, Journal of Virology.

[40]  John D Minna,et al.  Molecular biology of lung cancer: clinical implications. , 2002, Clinics in chest medicine.

[41]  Ming You,et al.  Wildtype Kras2 can inhibit lung carcinogenesis in mice , 2001, Nature Genetics.

[42]  P. Maloney,et al.  Cancer-specific genomic instability in bronchial lavage: a molecular tool for lung cancer detection. , 2001, Cancer research.

[43]  G. Kollias,et al.  TNF-α Induction by LPS Is Regulated Posttranscriptionally via a Tpl2/ERK-Dependent Pathway , 2000, Cell.

[44]  Philip Hahnfeldt,et al.  Cancer: looking outside the genome , 2000, Nature Reviews Molecular Cell Biology.

[45]  T L Chenevert,et al.  Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[46]  T. Jacks,et al.  Modeling human lung cancer in mice: similarities and shortcomings , 1999, Oncogene.

[47]  P. Tsichlis,et al.  The Tpl-2 protooncoprotein activates the nuclear factor of activated T cells and induces interleukin 2 expression in T cell lines. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[48]  N. Copeland,et al.  Tpl-2 is an oncogenic kinase that is activated by carboxy-terminal truncation. , 1997, Genes & development.

[49]  Z. Xie,et al.  Isolation and characterization of the human nucleophosmin/B23 (NPM) gene: identification of the YY1 binding site at the 5' enhancer region. , 1997, Nucleic acids research.

[50]  D. Pappin,et al.  Activation of MEK‐1 and SEK‐1 by Tpl‐2 proto‐oncoprotein, a novel MAP kinase kinase kinase. , 1996, The EMBO journal.

[51]  K. Sugimachi,et al.  ras gene mutations as a prognostic marker in adenocarcinoma of the human lung without lymph node metastasis. , 1992, Cancer research.

[52]  A. Malkinson.  Primary lung tumors in mice: an experimentally manipulable model of human adenocarcinoma. , 1992, Cancer research.

[53]  S. Rodenhuis,et al.  K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. , 1990, The New England journal of medicine.

[54]  A. Cassidy,et al.  Hypomethylation of retrotransposable elements correlates with genomic instability in non‐small cell lung cancer , 2009, International journal of cancer.

[55]  B. Fingleton,et al.  Epithelial NF-kappaB activation promotes urethane-induced lung carcinogenesis. , 2007, Proceedings of the National Academy of Sciences of the United States of America.

[56]  S. Howell,et al.  NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity. , 2003, Molecular and cellular biology.

[57]  G. Kollias,et al.  TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. , 2000, Cell.

[58]  H. Hansen,et al.  Lung cancer. , 1990, Cancer chemotherapy and biological response modifiers.