Carcinoma-associated eIF3i overexpression facilitates mTOR-dependent growth transformation.
Molecular processes controlling mRNA translation are complex, multilayered, and their deregulation can lead to cancer pathogenesis. Eukaryotic initiation factor 3 (eIF3) is involved in the initiation process of protein translation and overexpression of its subunit eukaryotic translation initiation factor i (eIF3i) has been observed in carcinomas. Nevertheless, the potential role of eIF3i in carcinogenesis is poorly understood. Here, we show that in vitro overexpression of human eIF3i resulted in cell size increase, proliferation enhancement, cell-cycle progression, and anchorage-independent growth. Without external stimuli, eIF3i overexpressing cells arrested in G1/G0 phase, demonstrating the requirement of additional growth signals. Inhibition of the kinase mTOR, a key player in the integration of nutrition and growth signals into protein synthesis, with rapamycin reduced serine phosphorylation of eIF3i and resulted in a loss of anchorage-independent growth. Thus, eIF3i overexpression fosters the integration of growth signals by mTOR into the mRNA translation process, promoting protein synthesis and tumor growth.
Ahlemann
Martin
M
Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
Zeidler
Reinhard
R
Lang
Stephan
S
Mack
Brigitte
B
Münz
Markus
M
Gires
Olivier
O
D000595:Amino Acid Sequence; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry; D049109:Cell Proliferation; D048429:Cell Size; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000032:analysis; D039621:Eukaryotic Initiation Factor-3 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017384:Sequence Deletion; D058570:TOR Serine-Threonine Kinases; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000032:analysis
D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases; D039621:Eukaryotic Initiation Factor-3; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; D016212:Transforming Growth Factor beta; C517819:PRKAR2A protein, human; C546842:MTOR protein, human