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PNAS 110 (16): 1470-1479

Copyright © 2013 by the National Academy of Sciences.

PNAS Plus


PNAS PLUS / BIOLOGICAL SCIENCES / MEDICAL SCIENCES

TPL2 kinase is a suppressor of lung carcinogenesis

Katerina Gkirtzimanakia,b,1, Kalliopi K. Gkouskoub,1, Urszula Oleksiewiczc, Georgios Nikolaidisc, Dimitra Vyrlaa,b, Michalis Liontosd, Vassiliki Pelekanoue, Dimitris C. Kanellisa,b, Kostantinos Evangeloud, Efstathios N. Stathopoulose, John K. Fieldc, Philip N. Tsichlisf, Vassilis Gorgoulisd, Triantafillos Liloglouc,2, and Aristides G. Eliopoulosa,b,2

aMolecular and Cellular Biology Laboratory, Division of Basic Sciences and eDepartment of Pathology, University of Crete Medical School, 710 03 Heraklion, Greece; bLaboratory of Cancer Biology, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas (FORTH), 700 13 Heraklion, Crete, Greece; cDepartment of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L3 9TA, United Kingdom; dMolecular Carcinogenesis Group, Department of Histology and Embryology, Medical School of Athens, 115 27 Athens, Greece; and fMolecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111

2To whom correspondence may be addressed. E-mail: eliopag{at}imbb.forth.gr or T.Liloglou{at}liverpool.ac.uk.

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.


 

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

See full research article on page E1470 of www.pnas.org.

Cite this Author Summary as: PNAS 10.1073/pnas.1215938110.


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