title: Nerve and epidermal growth factor induce protein synthesis and eIF2B activation in PC12 cells.
abstract: The regulation of protein synthesis and of eukaryotic initiation factor eIF2B was studied in PC12 cells. An increase in protein synthesis was observed after nerve growth factor (NGF) and epidermal growth factor (EGF) treatment of PC12 cells, and this increase coincided with activation of eIF2B. Growth factor addition in the presence of the phosphatidylinositol-3'-OH kinase inhibitor wortmannin showed that both NGF- and EGF-induced protein synthesis and eIF2B activation were phosphatidylinositol-3'-OH kinase dependent. The EGF-induced stimulation of protein synthesis and activation of eIF2B was dependent upon FK506-binding protein-rapamycin-associated protein, as shown with the immunosuppressant rapamycin, whereas NGF induction was partially dependent upon FK506-binding protein-rapamycin-associated protein. The activities of two kinases that act on eIF2B, glycogen synthase kinase-3 and casein kinase II, were measured to assess their potential roles in the activation of eIF2B in PC12 cells. Inactivation of glycogen synthase kinase-3 was seen in response to both NGF and EGF and this coincided with activation of eIF2B. However, inactivation of glycogen synthase kinase-3 was not rapamycin sensitive, in contrast to the activation of eIF2B. This indicates the involvement of another protein kinase or regulatory mechanism in the eIF2B activation. Both growth factors activated casein kinase II. However, the time course of its activation and its insensitivity to wortmannin and rapamycin suggest that casein kinase II does not play a major regulatory role in eIF2B activation under these conditions.
authors.affiliation: Department of Molecular Cell Biology, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Kleijn
authors.forename: G I
authors.initials: GI
authors.lastname: Welsh
authors.forename: G C
authors.initials: GC
authors.lastname: Scheper
authors.forename: H O
authors.initials: HO
authors.lastname: Voorma
authors.forename: C G
authors.initials: CG
authors.lastname: Proud
authors.forename: A A
authors.initials: AA
authors.lastname: Thomas
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000502:physiology; D047390:Casein Kinase II; D004268:DNA-Binding Proteins / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D020717:Eukaryotic Initiation Factor-2B; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D020662:Guanine Nucleotide Exchange Factors; D006360:Heat-Shock Proteins / Q000502:physiology; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016716:PC12 Cells / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011090:Polyenes / Q000494:pharmacology; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D038601:Ribosomal Protein S6; D012269:Ribosomal Proteins / Q000378:metabolism; D020123:Sirolimus; D022021:Tacrolimus Binding Proteins; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002352:Carrier Proteins; D047390:Casein Kinase II; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D020717:Eukaryotic Initiation Factor-2B; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D020662:Guanine Nucleotide Exchange Factors; D006360:Heat-Shock Proteins; D009414:Nerve Growth Factors; D019869:Phosphatidylinositol 3-Kinases; D011090:Polyenes; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D038601:Ribosomal Protein S6; D012269:Ribosomal Proteins; D020123:Sirolimus; D022021:Tacrolimus Binding Proteins; D000077191:Wortmannin