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Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):E1470-9. doi: 10.1073/pnas.1215938110. Epub 2013 Mar 26.

TPL2 kinase is a suppressor of lung carcinogenesis.

Author information

  • 1Molecular and Cellular Biology Laboratory, Division of Basic Sciences and Department of Pathology, University of Crete Medical School, 710 03 Heraklion, Greece.

Abstract

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.

PMID:
23533274
PMCID:
PMC3631618
DOI:
10.1073/pnas.1215938110
[PubMed - indexed for MEDLINE]
Free PMC Article
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