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Institute of Experimental Medicine (B.G.), Department of Neurobiology, Budapest H-1083, and University of Pécs, Faculty of Sciences, Institute of Biology, Pécs H-7624, Hungary; Szent István University (A.K.), Faculty of Veterinary Science, Department of Physiology and Biochemistry, Budapest H-1078, Hungary; Thyroid Division (B.G., J.W.H., P.R.L.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Dr. P. Reed Larsen, Thyroid Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Room 560, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115. E-mail: larsen{at}rascal.med.harvard.edu.
Type 2 deiodinase (D2) is a selenoenzyme catalyzing the activation of T4 to T3. D2 activity/mRNA ratios are often low, suggesting that there is significant posttranscriptional regulation. The D2 mRNA in higher vertebrates is more than 6 kb, containing long 5' and 3' untranslated regions (UTRs). The D2 5'UTRs are greater than 600 nucleotides and contain 3–5 short open reading frames. These full-length 5'UTRs reduce the D2 translation efficiency approximately 5-fold. The inhibition by human D2 5'UTR is localized to a region containing the first short open reading frame encoding a tripeptide—MKG. This inhibition was abolished by mutating the AUG start codon and weakened by modification of the essential purine of the Kozak consensus. Deletion of the 3.7-kb 3'UTR of the chicken D2 mRNA increased D2 activity approximately 3.8-fold due to an increase in D2 mRNA half-life. In addition, alternatively spliced D2 mRNA transcripts similar in size to the major 6- to 7-kb D2 mRNAs but not encoding an active enzyme are present in both human and chicken tissues. Our results indicate that a number of factors reduce the D2 protein levels. These mechanisms, together with the short half-life of the protein, ensure limited expression of this key regulator of T4 activation.
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