The role of polyamines in supporting growth of mammalian cells is mediated through their requirement for translation initiation and elongation.
Polyamines are essential cell constituents whose depletion results in growth cessation. Here we have investigated potential mechanisms of action of polyamines in supporting mammalian cell proliferation. We demonstrate that polyamines regulate translation both at the initiation and at the elongation steps. L-alpha-difluoromethylornithine treatment resulting in polyamine depletion reduces protein synthesis via inhibition of translation initiation. N1-guanyl-diaminoheptane (GC7), a spermidine analogue that inhibits eukaryotic initiation factor 5A (eIF5A) hypusination, also caused inhibition of translation initiation. In contrast, depletion of eIF5A by short hairpin RNA inhibits translation elongation as was recently demonstrated in yeast and Drosophila. These results suggest that in addition to competing with spermidine in the hypusination reaction, GC7 also competes with spermidine at yet undefined sites required for translation initiation. Finally, we show that either polyamine depletion or GC7 treatment induced eIF2alpha phosphorylation and reduced phosphorylation of 4E-BP, thus setting the molecular basis for the observed inhibition of translation initiation.
Landau
Guy
G
Department of Molecular Genetics, the Weizmann Institute of Science, Rehovot 76199, Israel.
Bercovich
Zippi
Z
Park
Myung Hee
MH
Kahana
Chaim
C
D000818:Animals; D049109:Cell Proliferation; D004330:Drosophila / Q000378:metabolism; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010441:Peptide Chain Elongation, Translational / Q000187:drug effects / Q000502:physiology*; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects / Q000502:physiology*; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D013095:Spermidine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015003:Yeasts / Q000378:metabolism; D000097574:Eukaryotic Translation Initiation Factor 5A
D000518:Eflornithine; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D006147:Guanine; D010448:Peptide Initiation Factors; D016601:RNA-Binding Proteins; D013095:Spermidine; D000097574:Eukaryotic Translation Initiation Factor 5A; C100667:N(1)-guanyl-1,7-diaminoheptane