title: Depression of neuronal protein synthesis initiation by protein tyrosine kinase inhibitors.
abstract: Growth factors stimulate cellular protein synthesis, but the intracellular signaling mechanisms that regulate initiation of mRNA translation in neurons have not been clarified. A rate-limiting step in the initiation of protein synthesis is the formation of the ternary complex among GTP, eukaryotic initiation factor 2 (eIF-2), and the initiator tRNA. Here we report that genistein, a specific tyrosine kinase inhibitor, decreases tyrosine kinase activity and the content of phosphotyrosine proteins in cultured primary cortical neurons. Genistein inhibits protein synthesis by > 80% in a dose-dependent manner (10-80 micrograms/ml) and concurrently decreases ternary complex formation by 60%. At the doses investigated, genistein depresses tyrosine kinase activity and concomitantly stimulates PKC activity. We propose that a protein tyrosine kinase participates in the initiation of protein synthesis in neurons, by affecting the activity of eIF-2 directly or through a protein kinase cascade.
authors.affiliation: Laboratory for Experimental Brain Research, University of Lund, Lund Hospital, Sweden.
authors.forename: B R
authors.initials: BR
authors.lastname: Hu
authors.forename: Y B
authors.initials: YB
authors.lastname: Yang
authors.forename: T
authors.initials: T
authors.lastname: Wieloch
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002250:Carbon Radioisotopes; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology*; D004622:Embryo, Mammalian; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D019833:Genistein; D006160:Guanosine Triphosphate / Q000378:metabolism; D007529:Isoflavones / Q000494:pharmacology*; D007930:Leucine / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000378:metabolism*; D012358:RNA, Transfer, Met / Q000378:metabolism; D051381:Rats
chemical_list: D002250:Carbon Radioisotopes; D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; D007529:Isoflavones; D009419:Nerve Tissue Proteins; D010636:Phenols; D012333:RNA, Messenger; D012358:RNA, Transfer, Met; C062898:lavendustin A; C067472:methyl 2,5-dihydroxycinnamate; D006160:Guanosine Triphosphate; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D007930:Leucine