TY - JOUR
T1 - Differential Requirements for eIF4E Dose in Normal Development and Cancer
AU - Truitt, Morgan L.
AU - Conn, Crystal S.
AU - Shi, Zhen
AU - Pang, Xiaming
AU - Tokuyasu, Taku
AU - Coady, Alison M.
AU - Seo, Youngho
AU - Barna, Maria
AU - Ruggero, Davide
N1 - Funding Information:
We thank members of the D.R. and M.B. labs for critical discussion and Adam Olshen for reading the manuscript. This work was supported by the NIH Director’s New Innovator Award (7DP2OD00850902) (to M.B.), NIH grants (R01CA140456, R01CA154916, and R01CA184624 to D.R.; 1F32CA189696 to C.S.C.; and P30CA82103 to T.T.), the Alfred P. Sloan Research Fellowship (to M.B), the Mallinckrodt Foundation Award (to M.B.), a Pew Scholars Award (to M.B.), an American Cancer Society grant (PF-14-212-01-RMC) (to C.S.C.), and the Life Science Research Foundation Postdoctoral Fellowship (to Z.S). This work was supported in part by the Onyx Oncology Innovation Alliance Award (to D.R.). D.R. is a Leukemia and Lymphoma Society Scholar. M.B. is a Pew Scholar and Alfred P. Sloan Research Fellow. D.R. is a shareholder of eFFECTOR Therapeutics, Inc., and a member of its scientific advisory board.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/7/2
Y1 - 2015/7/2
N2 - eIF4E, the major cap-binding protein, has long been considered limiting for translating the mammalian genome. However, the eIF4E dose requirement at an organismal level remains unexplored. By generating an Eif4e haploinsufficient mouse, we found that a 50% reduction in eIF4E expression, while compatible with normal development and global protein synthesis, significantly impeded cellular transformation. Genome-wide translational profiling uncovered a translational program induced by oncogenic transformation and revealed a critical role for the dose of eIF4E, specifically in translating a network of mRNAs enriched for a unique 5′ UTR signature. In particular, we demonstrate that the dose of eIF4E is essential for translating mRNAs that regulate reactive oxygen species, fueling transformation and cancer cell survival in vivo. Our findings indicate eIF4E is maintained at levels in excess for normal development that are hijacked by cancer cells to drive a translational program supporting tumorigenesis.
AB - eIF4E, the major cap-binding protein, has long been considered limiting for translating the mammalian genome. However, the eIF4E dose requirement at an organismal level remains unexplored. By generating an Eif4e haploinsufficient mouse, we found that a 50% reduction in eIF4E expression, while compatible with normal development and global protein synthesis, significantly impeded cellular transformation. Genome-wide translational profiling uncovered a translational program induced by oncogenic transformation and revealed a critical role for the dose of eIF4E, specifically in translating a network of mRNAs enriched for a unique 5′ UTR signature. In particular, we demonstrate that the dose of eIF4E is essential for translating mRNAs that regulate reactive oxygen species, fueling transformation and cancer cell survival in vivo. Our findings indicate eIF4E is maintained at levels in excess for normal development that are hijacked by cancer cells to drive a translational program supporting tumorigenesis.
UR - http://www.scopus.com/inward/record.url?scp=84934438925&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84934438925&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2015.05.049
DO - 10.1016/j.cell.2015.05.049
M3 - Article
C2 - 26095252
AN - SCOPUS:84934438925
SN - 0092-8674
VL - 162
SP - 59
EP - 71
JO - Cell
JF - Cell
IS - 1
ER -