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S-Nitrosylation of NF-κB p65 Inhibits TSH-Induced Na+/I− Symporter Expression

2015; Oxford University Press; Volume: 156; Issue: 12 Linguagem: Inglês

10.1210/en.2015-1192

1945-7170

Juan P. Nicola, Victoria Peyret, Magalí Nazar, Jorge M. Romero, Ariel Maximiliano Lucero, María del Mar Montesinos, José Luís Bocco, Claudia G. Pellizas, Ana M. Masini‐Repiso,

Cancer, Hypoxia, and Metabolism

Nitric oxide (NO) is a ubiquitous signaling molecule involved in a wide variety of cellular physiological processes. In thyroid cells, NO-synthase III-endogenously produced NO reduces TSH-stimulated thyroid-specific gene expression, suggesting a potential autocrine role of NO in modulating thyroid function. Further studies indicate that NO induces thyroid dedifferentiation, because NO donors repress TSH-stimulated iodide (I−) uptake. Here, we investigated the molecular mechanism underlying the NO-inhibited Na+/I− symporter (NIS)-mediated I− uptake in thyroid cells. We showed that NO donors reduce I− uptake in a concentration-dependent manner, which correlates with decreased NIS protein expression. NO-reduced I− uptake results from transcriptional repression of NIS gene rather than posttranslational modifications reducing functional NIS expression at the plasma membrane. We observed that NO donors repress TSH-induced NIS gene expression by reducing the transcriptional activity of the nuclear factor-κB subunit p65. NO-promoted p65 S-nitrosylation reduces p65-mediated transactivation of the NIS promoter in response to TSH stimulation. Overall, our data are consistent with the notion that NO plays a role as an inhibitory signal to counterbalance TSH-stimulated nuclear factor-κB activation, thus modulating thyroid hormone biosynthesis.