Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 8455-8462 |
| Number of pages | 8 |
| Journal | Cancer Research |
| Volume | 69 |
| Issue number | 21 |
| DOIs | |
| State | Published - Nov 1 2009 |
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Eukaryotic initiation factor 4E binding protein family of proteins : Sentinels at a translational control checkpoint in lung tumor defense. / Kim, Yong Y.; von Weymarn, Linda B; Larsson, Ola; Fan, Danhua; Underwood, Jon M.; Peterson, Mark S.; Hecht, Stephen S; Polunovsky, Vitaly A; Bitterman, Peter B.
In: Cancer Research, Vol. 69, No. 21, 01.11.2009, p. 8455-8462.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Eukaryotic initiation factor 4E binding protein family of proteins
T2 - Sentinels at a translational control checkpoint in lung tumor defense
AU - Kim, Yong Y.
AU - von Weymarn, Linda B
AU - Larsson, Ola
AU - Fan, Danhua
AU - Underwood, Jon M.
AU - Peterson, Mark S.
AU - Hecht, Stephen S
AU - Polunovsky, Vitaly A
AU - Bitterman, Peter B
PY - 2009/11/1
Y1 - 2009/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=70350521683&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70350521683&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-09-1923
DO - 10.1158/0008-5472.CAN-09-1923
M3 - Article
C2 - 19843855
AN - SCOPUS:70350521683
VL - 69
SP - 8455
EP - 8462
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 21
ER -