Hepatic translation control in the late-gestation fetal rat.
We have investigated the regulation of translation during the period of rapid liver growth that occurs at the end of gestation in the rat. This work was based on our prior observation that fetal hepatocyte proliferation is resistant to the inhibitory effects of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), a nutrient-sensing kinase that controls ribosome biogenesis and protein translation. We hypothesized that translation control in late-gestation fetal liver differs from that in adult liver. We first examined the ability of rapamycin to inhibit the translation of mRNAs encoding ribosomal proteins. Consistent with the effect of rapamycin on proliferation, the activation of adult liver 5'-terminal oligopyrimidine tracts (5'-TOP) translation that occurred during refeeding after food deprivation was sensitive to rapamycin. Fetal liver 5'-TOP translation was insensitive. We went on to examine the eukaryotic initiation factor (eIF) 4F cap-binding complex that controls global protein synthesis. The molecular weights of the multiple eIF4G1 isoforms present in fetal and adult liver eIF4F complexes differed. In addition, fetal liver expressed the eIF4A1 form of the eIF4A helicase, whereas adult liver contained eIF4A1 and eIF4A2. Rapamycin administration before refeeding in adult rats inhibited formation of the preinitiation complex to a much greater degree than rapamycin administration to fetal rats in situ. We conclude that there are major structural and functional differences in translation control between late-gestation fetal and adult liver. These differences may confer differential sensitivity to the growth inhibitory effects of rapamycin.
Division of Pediatric Endocrinology and Metabolism, Rhode Island Hospital, 593 Eddy St., Providence, RI 02903, USA. Philip_Gruppuso@brown.edu
Philip A
PA
Gruppuso
Shu-Whei
SW
Tsai
Joan M
JM
Boylan
Jennifer A
JA
Sanders
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004435:Eating; D039601:Eukaryotic Initiation Factor-4A / Q000235:genetics; D039562:Eukaryotic Initiation Factor-4F / Q000235:genetics; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics; D005260:Female; D005508:Food Deprivation; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005865:Gestational Age; D006498:Hepatectomy; D008099:Liver / Q000187:drug effects / Q000196:embryology* / Q000201:enzymology / Q000601:surgery; D008115:Liver Regeneration / Q000235:genetics; D008297:Male; D011247:Pregnancy; D014176:Protein Biosynthesis / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D038641:RNA 5' Terminal Oligopyrimidine Sequence; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D038601:Ribosomal Protein S6 / Q000235:genetics; D012269:Ribosomal Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
D039562:Eukaryotic Initiation Factor-4F; D039603:Eukaryotic Initiation Factor-4G; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D038601:Ribosomal Protein S6; D012269:Ribosomal Proteins; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D039601:Eukaryotic Initiation Factor-4A; D020123:Sirolimus