title: Nitric oxide-repressed Forkhead factor FoxE1 expression is involved in the inhibition of TSH-induced thyroid peroxidase levels.
abstract: Thyroid peroxidase (TPO) is essential for thyroid hormone synthesis mediating the covalent incorporation of iodine into tyrosine residues of thyroglobulin process known as organification. Thyroid-stimulating hormone (TSH) via cAMP signaling is the main hormonal regulator of TPO gene expression. In thyroid cells, TSH-stimulated nitric oxide (NO) production inhibits TSH-induced thyroid-specific gene expression, suggesting a potential autocrine role of NO in modulating thyroid function. Indeed, NO donors downregulate TSH-induced iodide accumulation and organification in thyroid cells. Here, using FRTL-5 thyroid cells as model, we obtained insights into the molecular mechanism underlying the inhibitory effects of NO on iodide organification. We demonstrated that NO donors inhibited TSH-stimulated TPO expression by inducing a cyclic guanosine monophosphate-dependent protein kinase-mediated transcriptional repression of the TPO gene. Moreover, we characterized the FoxE1 binding site Z as mediator of the NO-inhibited TPO expression. Mechanistically, we demonstrated that NO decreases TSH-induced FoxE1 expression, thus repressing the transcripcional activation of TPO gene. Taken together, we provide novel evidence reinforcing the inhibitory role of NO on thyroid cell function, an observation of potential pathophysiological relevance associated with human thyroid pathologies that come along with changes in the NO production.
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología - Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: María del Mar
authors.initials: Mdel M
authors.lastname: Montesinos
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología - Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Nicola
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología - Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Magalí
authors.initials: M
authors.lastname: Nazar
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología - Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Victoria
authors.initials: V
authors.lastname: Peyret
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología - Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Ariel Maximiliano
authors.initials: AM
authors.lastname: Lucero
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología - Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Claudia Gabriela
authors.initials: CG
authors.lastname: Pellizas
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología - Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina. Electronic address: amasini@fcq.unc.edu.ar.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Masini-Repiso
mesh_terms: D000818:Animals; D002417:Cattle; D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009573:Nitrites / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013972:Thyrotropin / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D051858:Forkhead Transcription Factors; C526350:FoxE1 protein, rat; D020030:Nitric Oxide Donors; D009573:Nitrites; D009569:Nitric Oxide; D013972:Thyrotropin; D000242:Cyclic AMP; D007453:Iodide Peroxidase; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP
keywords: Forkhead box protein E1 (FoxE1); Nitric oxide (NO); Thyroid stimulating hormone (TSH); Thyroperoxidase (TPO)