title: The 4E-BP-eIF4E axis promotes rapamycin-sensitive growth and proliferation in lymphocytes.
abstract: Rapamycin has been used as a clinical immunosuppressant for many years; however, the molecular basis for its selective effects on lymphocytes remains unclear. We investigated the role of two canonical effectors of the mammalian target of rapamycin (mTOR): ribosomal S6 kinases (S6Ks) and eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs). S6Ks are thought to regulate cell growth (increase in cell size), and 4E-BPs are thought to control proliferation (increase in cell number), with mTORC1 signaling serving to integrate these processes. However, we found that the 4E-BP-eIF4E signaling axis controlled both the growth and proliferation of lymphocytes, processes for which the S6Ks were dispensable. Furthermore, rapamycin disrupted eIF4E function selectively in lymphocytes, which was due to the increased abundance of 4E-BP2 relative to that of 4E-BP1 in these cells and the greater sensitivity of 4E-BP2 to rapamycin. Together, our findings suggest that the 4E-BP-eIF4E axis is uniquely rapamycin-sensitive in lymphocytes and that this axis promotes clonal expansion of these cells by coordinating growth and proliferation.
authors.affiliation: Department of Molecular Biology and Biochemistry, and Institute for Immunology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Lomon
authors.initials: L
authors.lastname: So
authors.affiliation: Department of Molecular Biology and Biochemistry, and Institute for Immunology, University of California, Irvine, Irvine, CA 92697, USA. Department of Medicine, University of California, San Diego, San Diego, CA 92103, USA.
authors.forename: Jongdae
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Molecular Biology and Biochemistry, and Institute for Immunology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Palafox
authors.affiliation: Department of Molecular Biology and Biochemistry, and Institute for Immunology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Mallya
authors.affiliation: Department of Molecular Biology and Biochemistry, and Institute for Immunology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Chaz G
authors.initials: CG
authors.lastname: Woxland
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Meztli
authors.initials: M
authors.lastname: Arguello
authors.affiliation: School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Morgan L
authors.initials: ML
authors.lastname: Truitt
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.affiliation: School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
authors.affiliation: Department of Molecular Biology and Biochemistry, and Institute for Immunology, University of California, Irvine, Irvine, CA 92697, USA. dfruman@uci.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Fruman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D049108:Cell Enlargement; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D003433:Crosses, Genetic; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors; D005260:Female; D005786:Gene Expression Regulation; D006160:Guanosine Triphosphate; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C411571:EIF4ENIF1 protein, human; C499527:Eif4ebp1 protein, mouse; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D007166:Immunosuppressive Agents; D029543:Nucleocytoplasmic Transport Proteins; D010750:Phosphoproteins; C000601282:eIF4E protein, mouse; D006160:Guanosine Triphosphate; D020123:Sirolimus