TPL2 kinase is a suppressor of lung carcinogenesis

Katerina Gkirtzimanaki, Kalliopi K Gkouskou, Urszula Oleksiewicz, Georgios Nikolaidis, Dimitra Vyrla, Michalis Liontos, Vassiliki Pelekanou, Dimitris C Kanellis, Kostantinos Evangelou, Efstathios N Stathopoulos, John K Field, Philip N Tsichlis, Vassilis Gorgoulis, Triantafillos Liloglou, Aristides G Eliopoulos

Research output: Contribution to journalArticle (journal)peer-review

43 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)E1470-9
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number16
Publication statusPublished - 16 Apr 2013


  • Animals
  • Base Sequence
  • Cell Transformation, Neoplastic/genetics
  • DNA Methylation
  • DNA Mutational Analysis
  • DNA Primers/genetics
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic/immunology
  • Humans
  • Immunoblotting
  • Lung Neoplasms/immunology
  • MAP Kinase Kinase Kinases/genetics
  • Mice
  • MicroRNAs/metabolism
  • Molecular Sequence Data
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins/genetics
  • Sequence Analysis, DNA
  • ras Proteins/metabolism


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