Translational initiation regulators are hypophosphorylated in rat liver during ethionine-mediated ATP depletion.
Administration of ethionine to female rats is known to inhibit hepatic protein synthesis by reducing the level of hepatic ATP. Administration of methionine and/or adenine rapidly restores the ATP levels and protein synthesis. The ethionine administration causes a progressive disaggregation of hepatic polysomes, suggesting that the initiation step of protein synthesis is inhibited. Recent studies indicate that changes in initiation are associated with alterations in the phosphorylation states of translational initiation regulators such as eukaryotic initiation factor (eIF) 4E, eIF4E-binding protein 1 (4E-BP1), and the 70-kDa ribosomal protein S6 kinase (S6K1). We found that these initiation regulators are hypophosphorylated in rat liver during ethionine-mediated ATP depletion (60% of the control value). Furthermore, the restoration of the ATP levels by the administration of methionine and adenine brought about a complete recovery of the phosphorylation states of all these regulators. The present data suggest that hypophosphorylation of various initiation regulators represents the primary event in the ethionine-induced breakdown of polysomes and inhibition of protein synthesis in the liver. Possible involvement of mammalian target of rapamycin (mTOR), as a sensor of intracellular ATP level, was also discussed.
Yoshizawa
Fumiaki
F
Department of Animal Science, Utsunomiya University, 350 Mine-machi, Tochigi 321-8505, Japan. fumiaki@cc.utsunomiya-u.ac.jp
Watanabe
Emi
E
Sugahara
Kunio
K
Natori
Yasuo
Y
D000255:Adenosine Triphosphate / Q000032:analysis*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D005001:Ethionine / Q000494:pharmacology*; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000737:chemistry / Q000378:metabolism*; D010448:Peptide Initiation Factors / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism
D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D011500:Protein Synthesis Inhibitors; D000255:Adenosine Triphosphate; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D005001:Ethionine