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Eukaryotic Initiation Factor 4E Binding Protein Family of Proteins: Sentinels at a Translational Control Checkpoint in Lung Tumor Defense

Departments of ¹ Medicine, ² Biochemistry, Molecular Biology and Biophysics, ³ Biostatistics and Informatics, ⁴ Pharmacology, and ⁵ Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota; and ⁶ Department of Biochemistry, McGill University, Montreal, Quebec, Canada

Requests for reprints: Yong Y. Kim and Peter B. Bitterman, Department of Medicine, University of Minnesota Medical School, 420 Delaware Street Southeast, MMC 276, Minneapolis, MN 55455. Phone: 612-626-2736; Fax: 612-625-2174; E-mail: kimxx327{at}umn.edu and bitte001{at}umn.edu.

The usurping of translational control by sustained activation of translation initiation factors is oncogenic. Here, we show that the primary negative regulators of these oncogenic initiation factors—the 4E-BP protein family—operate as guardians of a translational control checkpoint in lung tumor defense. When challenged with the tobacco carcinogen 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (NNK), 4ebp1^–/–/4ebp2^–/– mice showed increased sensitivity to tumorigenesis compared with their wild-type counterparts. The 4E-BP–deficient state per se creates pro-oncogenic, genome-wide skewing of the molecular landscape, with translational activation of genes governing angiogenesis, growth, and proliferation, and translational activation of the precise cytochrome p450 enzyme isoform (CYP2A5) that bioactivates NNK into mutagenic metabolites. Our study provides in vivo proof for a translational control checkpoint in lung tumor defense. [Cancer Res 2009;69(21):8455–62]

Key Words: Lung Cancer • NNK • Translational Control