Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid hormone action on brain development is essentially exerted through regulation of the expression rate of a number of genes some of which have been identified in the past 10 years. In the present work we describe the thyroid hormone regulation of a novel Ras homolog which we have named Rhes (Ras homolog enriched in striatum). The rhes cDNA was previously isolated in subtractive hybridization experiments aimed at identifying cDNA clones corresponding to genes expressed preferentially in the rat striatum. The sequence was found to encode a small GTP-binding protein of the Ras family with highest homology to the dexamethasone-inducible Dexras1. Here we show that rhes mRNA and protein in the striatum are strongly dependent on the thyroidal status. Developmentally, Rhes was regulated such that in normal rats there was an increased rhes mRNA content in the striatum after postnatal day 5 (P5). Rhes concentration in hypothyroid rats was similar to that of normal rats at P5, but the subsequent age-dependent increase was blunted. The administration of a single T3 dose to hypothyroid rats normalized rhes mRNA concentration in 8 h, whereas it took 24 h, or more, to normalize the expression of rc3, another T3-dependent brain gene, involved in PKC signaling. Double in situ hybridization using rhes and rc3 riboprobes showed that the bulk of rhes signal was located in cells expressing rc3. Given the relevance of small GTPases in signal transduction it is very likely that control of rhes, in addition to rc3, is of relevance to explain the actions of thyroid hormone in the striatum, a region of the brain especially vulnerable in neurological cretinism.
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PMID:Thyroid hormone regulation of rhes, a novel Ras homolog gene expressed in the striatum. 1159 59

Thyroperoxidase-catalyzed iodination of thyroglobulin and subsequent oxidative coupling of iodinated tyrosyl residues to protein-bound iodothyronines are the key reactions in thyroid hormone biosynthesis. Under sufficient iodine supply, both synthesis steps are rate-limited by the availability of hydrogen peroxide (H(2)O(2)), which is required as final electron acceptor. The primary enzyme feeding H(2)O(2) to thyroid peroxidase is a heterodimeric NADPH oxidase complex of dual oxidase 2 (DUOX2) and DUOX maturation factor 2 (DUOXA2) at the apical plasma membrane. While the thyrotropin receptor mediates most biological effects through the Gs/adenyl cyclase/cAMP pathway, the Gq/phospholipase C-beta cascade induces H(2)O(2) generation via synergistic effects of increased intracellular calcium and protein kinase C activation on DUOX2/DUOXA2. Defects in thyroidal H(2)O(2) generation have been identified in a subset of patients with congenital hypothyroidism. These include loss-of-function mutations in DUOX2 and DUOXA2. Thyrotropin receptor mutations with preferential loss of Gq-coupling may indirectly affect H(2)O(2) production. Expressivity of the defects can be highly variable owning to the presence of genetic modifiers (e.g., the paralogs DUOX1 and DUOXA1), and environmental factors particularly nutritional iodide intake.
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PMID:Defects of thyroidal hydrogen peroxide generation in congenital hypothyroidism. 2012 87