Increased turnover of the messenger RNA encoding tyrosine aminotransferase can account for the desensitization and de-induction of tyrosine aminotransferase by 8-bromo-cyclic AMP treatment and removal.
Treatment of H-4 rat hepatoma cells with 8-bromo-cyclic AMP (8-Br-cAMP) resulted in a transient induction of the gluconeogenic enzyme tyrosine aminotransferase. Synthesis of tyrosine aminotransferase and the level of its corresponding mRNA peaked 2 h after the addition of the cyclic nucleotide and declined thereafter. Tyrosine aminotransferase synthesis and mRNA failed to respond to the readdition of fresh 8-Br-cAMP, a process which we defined as desensitization. Removal of 8-Br-cAMP resulted in a decrease in tyrosine aminotransferase synthesis and mRNA, a process defined as de-induction. The relative transcription rate of the tyrosine aminotransferase gene and the turnover of its mRNA were determined by labeling intact cells with [3H]uridine. 8-Br-cAMP led to an increase in the rate of tyrosine aminotransferase transcription which was sustained for at least 4 h. The transcription rate declined upon de-induction. In addition, 8-Br-cAMP increased the turnover rate of tyrosine aminotransferase mRNA, but only after a 1.5-3 h time lag. This increased degradation rate persisted for at least 1.5 h after the removal of 8-Br-cAMP. These two contrasting and temporally distinct processes could account for the observed changes in tyrosine aminotransferase mRNA levels in response to 8-Br-cAMP treatment and removal.
Smith
J D
JD
Department of Pharmacology, Harvard Medical School, Boston, MA 02115.
Liu
A Y
AY
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern; D005786:Gene Expression Regulation / Q000187:drug effects*; D066298:In Vitro Techniques; D007700:Kinetics; D008114:Liver Neoplasms, Experimental; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014444:Tyrosine Transaminase / Q000235:genetics*; D014544:Uridine Triphosphate / Q000378:metabolism
D012333:RNA, Messenger; D015124:8-Bromo Cyclic Adenosine Monophosphate; D014444:Tyrosine Transaminase; D014544:Uridine Triphosphate