Ethionine-induced ATP depletion represses mTOR signaling in the absence of increases in AMP-activated protein kinase activity in the rat liver.
Administration of ethionine to female rats caused a rapid and severe decline in liver ATP and inhibited hepatic protein synthesis in association with hypophosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and 70-kDa ribosomal protein S6 kinase (S6K1), two key regulatory proteins involved in initiation of mRNA translation. Phosphorylation of both regulatory proteins is mediated through a signaling pathway that involves the mammalian target of rapamycin (mTOR). Recent studies indicate that AMP-activated protein kinase (AMPK) plays a role in the cellular response to environmental stresses, which deplete ATP, and suppresses protein synthesis through downregulated mTOR signaling. We investigated the possible involvement of AMPK in the ethionine-induced inhibition of protein synthesis. The administration of ethionine surprisingly decreased AMPK activity compared with controls despite ATP depletion. We conclude that inhibition of protein synthesis by ethionine is due to AMPK-independent inhibition of mTOR signaling following ATP depletion.
Yoshizawa
Fumiaki
F
Department of Animal Science, Utsunomiya University, Utsunomiya, Tochigi 321-8205, Japan. fumiaki@cc.utsunomiya-u.ac.jp
Mochizuki
Shinji
S
Doi
Masako
M
Yamaoka
Ippei
I
Sugahara
Kunio
K
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005001:Ethionine / Q000494:pharmacology*; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases
D000255:Adenosine Triphosphate; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005001:Ethionine