This is a new proposal to determine the mechanisms regulating the rate-limiting steps in the ubiquitin proteasome system leading to the controlled degradation of the Types 1, 2 and 3 selenodeiodinases. D2 is a critical enzyme regulating the first step in thyroid hormone action, the conversion of the prohormone T4 to the active hormone, T3. This process occurs intracellularly in brain, pituitary and brown fat in which the T3 produced constitutes a major fraction of the nuclear receptor-bound hormone. Furthermore, it appears that, in humans, unlike in adult rodents, D2 may also generate a significant fraction of plasma T3 by virtue of its wide tissue expression in skeletal muscle. It has been known for a number of years that post-translational regulation of D2 by substrate is a major regulatory step in determining the tissue level of the active enzyme. Recent studies have shown that degradation of D2 occurs in proteasomes, that its half-life is quite short (<1 hr), that its degradation is accelerated 2-fold by exposure to substrate and that this process requires interaction of substrate with a D2 enzyme which has either selenocysteine or cysteine in its active center. To define the regulatory steps in this process, the investigator will use several complementary systems. These include transient expression in HEK-293 cells and a temperature-sensitive CHO cell line containing a mutant UB-1 enzyme. A third strategy will be to exploit the fact that D2 can be expressed in yeast with well-documented mutations in the ubiquitin-proteasome degradation pathway and that it is possible to express both wild type and epitope-labeled protein to evaluate changes in activity those in D2 protein levels. Lastly, the investigator will employ cell-free systems which will allow the study of specific components of the ubiquitin proteasome system in the metabolism of D2 and compare results with those for Dl and D3 which have significantly longer half-lives. From a physiological perspective, it is quite conceivable that the accelerated proteolysis of D2 in human skeletal muscle during starvation or illness could explain the rapid onset of the """"""""low T3 syndrome."""""""" This is a well-recognized but poorly understood phenomenon which occurs in every human under food restriction or with significant systemic illness.
| Mohácsik, Petra; Erdélyi, Ferenc; Baranyi, Mária et al. (2018) A Transgenic Mouse Model for Detection of Tissue-Specific Thyroid Hormone Action. Endocrinology 159:1159-1171 |
| Yu, Guoying; Tzouvelekis, Argyris; Wang, Rong et al. (2018) Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nat Med 24:39-49 |
| Peterson, Sarah J; McAninch, Elizabeth A; Bianco, Antonio C (2016) Is a Normal TSH Synonymous With ""Euthyroidism"" in Levothyroxine Monotherapy? J Clin Endocrinol Metab 101:4964-4973 |
| McAninch, Elizabeth A; Bianco, Antonio C (2016) The History and Future of Treatment of Hypothyroidism. Ann Intern Med 164:50-6 |
| Gereben, Balázs; McAninch, Elizabeth A; Ribeiro, Miriam O et al. (2015) Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nat Rev Endocrinol 11:642-652 |
| McAninch, Elizabeth A; Jo, Sungro; Preite, Nailliw Z et al. (2015) Prevalent polymorphism in thyroid hormone-activating enzyme leaves a genetic fingerprint that underlies associated clinical syndromes. J Clin Endocrinol Metab 100:920-33 |
| Werneck de Castro, Joao Pedro; Fonseca, Tatiana L; Ueta, Cintia B et al. (2015) Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. J Clin Invest 125:769-81 |
| Bianco, Antonio C; Anderson, Grant; Forrest, Douglas et al. (2014) American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models. Thyroid 24:88-168 |
| Abdalla, Sherine M; Bianco, Antonio C (2014) Defending plasma T3 is a biological priority. Clin Endocrinol (Oxf) 81:633-41 |
| McAninch, Elizabeth A; Bianco, Antonio C (2014) Thyroid hormone signaling in energy homeostasis and energy metabolism. Ann N Y Acad Sci 1311:77-87 |
Showing the most recent 10 out of 45 publications
