CIBICI   14215
CENTRO DE INVESTIGACION EN BIOQUIMICA CLINICA E INMUNOLOGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Nitric Oxide-repressed Forkhead Factor FoxE1 expression inhibits the TSH-induced Thyroid Peroxidase levels.
Autor/es:
MONTESINOS, MM; NICOLA, JP; NAZAR, M; PEYRET, V; LUCERO, AM; PELLIZAS, CG; MASINI-REPISO, AM
Lugar:
Orlando
Reunión:
Congreso; 15th Internation Thyroid Congress; 2015
Institución organizadora:
American Thyroid Association
Resumen:
Thyroidperoxidase (TPO) is essential for thyroid hormone synthesis mediating thecovalent incorporation of iodine into tyrosine residues of thyroglobulin (I-organification) and the coupling of iodotyrosyl residues to form thyroid hormones. Thyrotropin (TSH) is the main hormonal regulator of TPO gene expression.The thyroid transcription factor FoxE1 is crucial for TSH-induced TPOexpression. Previous studies have indicatedthat nitric oxide (NO) represses TSH-induced I-transport and organification in thyroid cells. Moreover, NO donors inhibitTSH-induced TPO mRNA expression in the rat thyroid cell line FRTL-5. Here, we aimed tofurther explore the molecular mechanism underlying the inhibitory effects of NOon TPO expression.FRTL-5 cells wereincubated with different NO donors (sodium nitroprusside andS-nitrosoglutathione). TPO and FoxE1 expression was evaluated through western blot, RT/qPCR, and genereporter assays. FoxE1 binding to TPO promoter was evaluated by gel shiftassays and chromatin immunoprecipitation assays.NO donors decreasedTSH-induced TPO mRNA and protein expression. NO-reduced TPO expression resultedfrom transcriptional repression of the TPO gene in response to activation of guanosine monophosphate/solubleguanylate cyclase (cGMP/cGK) pathway. Deletion analysis of the TPO promoter revealed theFoxE1 binding site Z as mediator of the NO-repressed TPO promoter activity.Coincidently, NO donors decreased the TSH-stimulated FoxE1 binding to the TPOpromoter. Further characterization of the role of NO donors on FoxE1 expressionrevealed that NO donors reduced the TSH-stimulated FoxE1 levels byinhibiting FoxE1 gene expression. Interestingly, FoxE1 overexpression prevented the NOdonors-inhibited TPO expression in response to TSH. We demonstrated that NO-modulated TPO transcriptionalexpression involves NO-triggered inhibition of FoxE1 expression, which reducestransactivation of the TSH-stimulated TPO promoter. In addition, these results reinforce theregulatory role of NO on thyroid cell function, an observationof potential pathophysiological relevance associated withhuman thyroid pathologies associated with chronic NO production.