Date of Award


Degree Type


Degree Name

Doctor of Philosophy


The ornithine urea cycle enzymes, carbamyl phosphate synthetase (CPS-1), ornithine transcarbamylase (OTC) and arginase, are liver-specific proteins. Their expression is coordinately activated during the metamorphosis of the Rana catesbeiana tadpole by thyroid hormone (TH), and their presence is critical for the shift of this amphibian from an aquatic, ammonotelic larva into a terrestrial, ureotelic adult. My studies were focused on analyzing the transcriptional regulation of the genes encoding these urea cycle enzymes and determining whether these genes were upregulated directly or indirectly by TH. With this thought in mind, I isolated and characterized the sequences in the promoter regions of the CPS-1 and OTC genes and found that they lacked thyroid hormone response elements (TREs). This observation implies that TH is not directly regulating the expression of these genes. However, the presence of C/EBP (CAATT/enhancer binding protein) binding elements in the promoter regions of both of these genes prompted the thought that this transcription factor may be TH-inducible and play a role in the TH-indured expression of the CPS-1 and OTC genes. Thus, I isolated and characterized cDNAs encoding two different C/EBP-like proteins. One of them, RcC/EBP-1, encodes a Rana homologue of the mammalian C/EBP{dollar}\alpha{dollar}, and protein synthesized from it was found to bind specifically to the mammalian C/EBP-like sequences present in the Rana CPS-1 and OTC genes. Although no TREs are evident in the promoter region of this RcC/EBP-1 gene, Southern hybridizations suggest that more than one copy of this gene is present in the Rana genome and Northern hybridizations indicate that at least one of them is upregulated by TH. The TH-induced upregulation of an RcC/EBP-1 mRNA is concurrent with the upregulation of mRNAs encoding a thyroid hormone direct-response gene, TR{dollar}\beta{dollar}, and precedes, by at least 12 hours, the upregulation of mRNAs encoding CPS-1, OTC and arginase. These results imply that the TH-induced expression of urea cycle enzyme genes involves a cascade of molecular events in which a member of the RcC/EBP-1 family plays a role in orchestrating the expression of these genes in the liver of this tadpole during both spontaneous and TH-induced metamorphosis.



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