Depression of neuronal protein synthesis initiation by protein tyrosine kinase inhibitors.
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.
Hu
B R
BR
Laboratory for Experimental Brain Research, University of Lund, Lund Hospital, Sweden.
Yang
Y B
YB
Wieloch
T
T
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
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