Nitric Oxide-repressed Forhead factor FoxE1 expression is involved in the inhibition TSH-induced Thyroid Peroxidase levels

MONTESINOS MM; PEYRET V; NICOLA JP; PELLIZAS CG; NAZAR M; MASINI-REPISO AM

MOLECULAR AND CELLULAR ENDOCRINOLOGY.

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2016 vol. 420 p. 105 - 115

0303-7207

Thyroid peroxidase (TPO) is essential for thyroid hormone synthesis mediating the covalent incorporationof iodine into tyrosine residues of thyroglobulin process known as organification. Thyroidstimulatinghormone (TSH) via cAMP signaling is the main hormonal regulator of TPO gene expression.In thyroid cells, TSH-stimulated nitric oxide (NO) production inhibits TSH-stimulated thyroidspecificgene expression, suggesting a potential autocrine role of NO in modulating thyroid function.Indeed, NO donors downregulates TSH-induced iodide accumulation organification in thyroid cells. Here,using FRTL-5 thyroid cells as model, we obtained insights on the molecular mechanism underlying theinhibitory effects of NO on iodide organification. We demonstrated that NO donors inhibited TSHstimulatedTPO expression by inducing a cyclic guanosine monophosphate-dependent protein kinasemediatedtranscriptional repression of the TPO gene. Moreover, we characterized the FoxE1 bindingsite Z as mediator of the NO-inhibited TPO expression. Mechanistically, we demonstrated that NO decreasesTSH-induced FoxE1 expression, thus repressing the transcripcional activation of TPO gene. Takentogether, we provide novel evidence reinforcing the inhibitory role of NO on thyroid cell function, anobservation of potential pathophysiological relevance associated with human thyroid pathologies thatcome along with changes in the NO production.