Eukaryotic initiation factor 4E binding protein family of proteins: sentinels at a translational control checkpoint in lung tumor defense.
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.
Kim
Yong Y
YY
Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA. kimxx327@umn.edu
Von Weymarn
Linda
L
Larsson
Ola
O
Fan
Danhua
D
Underwood
Jon M
JM
Peterson
Mark S
MS
Hecht
Stephen S
SS
Polunovsky
Vitaly A
VA
Bitterman
Peter B
PB
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002352:Carrier Proteins / Q000502:physiology*; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018736:DNA Adducts / Q000235:genetics; D039642:Eukaryotic Initiation Factors / Q000502:physiology*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D046228:Microarray Analysis; D008861:Microsomes / Q000378:metabolism; D009389:Neovascularization, Pathologic; D009602:Nitrosamines / Q000633:toxicity; D010750:Phosphoproteins / Q000502:physiology*; D014176:Protein Biosynthesis; D012270:Ribosomes / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D002273:Carcinogens; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D018736:DNA Adducts; C499527:Eif4ebp1 protein, mouse; C491255:Eif4ebp2 protein, mouse; D039642:Eukaryotic Initiation Factors; D009602:Nitrosamines; D010750:Phosphoproteins; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D003577:Cytochrome P-450 Enzyme System