Inhibition of tyrosine aminotransferase gene expression by retinoic acid.
Regulation of tyrosine aminotransferase (TAT) gene expression was examined in RALA255-10G, a simian virus-40 tsA mutant-immortalized adult rat hepatocyte line. At the nonpermissive temperature (40 C), these hepatocytes exhibited a differentiated phenotype and actively expressed the TAT gene, but only in the presence of dexamethasone (DEX). The glucocorticoid-mediated TAT expression was inhibited by cycloheximide, a protein synthesis inhibitor, and by RU486, a glucocorticoid antagonist, suggesting that glucocorticoid induction requires protein synthesis and may be mediated through hormone receptors. (Bu)2cAMP (Bt2cAMP) or retinoic acid, individually or in combination, failed to increase TAT mRNA levels. However, Bt2cAMP greatly potentiated the induction by DEX, whereas retinoic acid inhibited the induction by DEX or DEX/Bt2cAMP. Nuclear run-on assays demonstrated that the induction of TAT expression by DEX or DEX/Bt2cAMP in RALA255-10G cells is regulated primarily at the transcriptional level. In contrast, retinoic acid antagonized the DEX- or DEX/Bt2cAMP-mediated induction without affecting the rate of TAT gene transcription. Instead, retinoic acid destabilized TAT mRNA. The half-life values of TAT mRNA in DEX/Bt2cAMP- and DEX/Bt2cAMP/retinoic acid-treated cells were approximately 235-270 min and 90-100 min, respectively. Our results indicate that inhibition of TAT expression by retinoic acid was regulated primarily at the posttranscriptional level.
Pan
C J
CJ
Human Genetics Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
Shelly
L L
LL
Rabin
D S
DS
Chou
J Y
JY
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002460:Cell Line; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000187:drug effects / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D015735:Mifepristone / Q000494:pharmacology; D010957:Plasmids; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*; D014444:Tyrosine Transaminase / Q000235:genetics*
D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D014212:Tretinoin; D003994:Bucladesine; D003907:Dexamethasone; D003513:Cycloheximide; D014444:Tyrosine Transaminase