NICOLA JUAN PABLO
Congresos y reuniones científicas
Título:
REGULATION OF THE NUCLEAR FACTOR NF-κB SIGNALING PATHWAY IN RESPONSE TO THYROIDSTIMULATING HORMONE RECEPTOR ACTIVATION
Autor/es:
NICOLA, JP; NAZAR, M; REALE, C; MARTIN, M; PEYRET, V; VITO, P; MASINI-REPISO, AM
Lugar:
Rio de Janeiro
Reunión:
Congreso; XVI Congreso de la Sociedad Latinoamericana de Tiroides; 2017
Institución organizadora:
Sociedad Latinoamericana de Tiroides
Resumen:
Introduction: Although activation of NF-κB signaling in thyroid follicular cells downstream to TSH receptor engagement
has been reported, the downstream signaling that result in NF-κB activation remain unexplored. Previously, we demonstrated
the participation of NF-κB in the upregulation of different genes involved in thyroid hormonogenesis in response to bacterial
lipopolysaccharide. Recent data demonstrated that genetic deletion of NEMO in the thyroid tissue lead to apoptotic death of
thyroid follicular cells. Objective: We sought to elucidate the mechanism that mediates NF-κB signaling activation in response
to the activation of the TSH receptor. Results and Discussion: TSH treatment leads to PKC-mediated phosphorylation of the
IKK regulatory complex, degradation of the cytosolic IκB-α inhibitor, and nuclear translocation of the NF-κB p65 subunit,
thus indicating activation of the canonical NF-κB signaling. Moreover, TSH stimulation phosphorylates the kinase TAK-1 and
its knock-down abolished TSH-induced IKK complex phosphorylation and the transcriptional activity of NF-κB. Although
PKA inhibition did not modulate TSH-induced nuclear recruitment of p65, TSH induces the transcriptional activity of the
NF-κB subunit p65 in a PKA-dependent phosphorylation on Ser-276. Additionally, p65 phosphorylation on Ser-276 induced
acetyl transferases CBP/p300 recruitment leading to its acetylation on Lys-310, thus enhancing its transcriptional activity.
Evaluation of the role played by NF-κB in thyroid physiology demonstrated that the NF-κB inhibitor BAY 11-7082 reduced
TSH-induced expression of the proteins involved in thyroid hormonogenesis Of note, the role of NF-κB in thyroid physiology
was confirmed assessing TSH-induced gene expression in primary cultures of NEMO-deficient thyrocytes. Moreover, chromatin
immunoprecipitation and knock-down experiments revealed that p65 is a transcriptional effector of TSH actions inducing
the expression of genes involved in thyroid hormonogenesis. Altogether our results point to NF-κB as a pivotal mediator in the
TSH-induced thyroid follicular cell differentiation. Increasing evidence indicates that NF-κB participates in the pathogenesis
of autoimmune diseases, being a key factor in the interface between inflammation and cancer. We speculate that a misbalance
in TSH signaling regulation could have potential implication in thyroid pathophysiology through the modulation of NF-κB
signaling.
has been reported, the downstream signaling that result in NF-κB activation remain unexplored. Previously, we demonstrated
the participation of NF-κB in the upregulation of different genes involved in thyroid hormonogenesis in response to bacterial
lipopolysaccharide. Recent data demonstrated that genetic deletion of NEMO in the thyroid tissue lead to apoptotic death of
thyroid follicular cells. Objective: We sought to elucidate the mechanism that mediates NF-κB signaling activation in response
to the activation of the TSH receptor. Results and Discussion: TSH treatment leads to PKC-mediated phosphorylation of the
IKK regulatory complex, degradation of the cytosolic IκB-α inhibitor, and nuclear translocation of the NF-κB p65 subunit,
thus indicating activation of the canonical NF-κB signaling. Moreover, TSH stimulation phosphorylates the kinase TAK-1 and
its knock-down abolished TSH-induced IKK complex phosphorylation and the transcriptional activity of NF-κB. Although
PKA inhibition did not modulate TSH-induced nuclear recruitment of p65, TSH induces the transcriptional activity of the
NF-κB subunit p65 in a PKA-dependent phosphorylation on Ser-276. Additionally, p65 phosphorylation on Ser-276 induced
acetyl transferases CBP/p300 recruitment leading to its acetylation on Lys-310, thus enhancing its transcriptional activity.
Evaluation of the role played by NF-κB in thyroid physiology demonstrated that the NF-κB inhibitor BAY 11-7082 reduced
TSH-induced expression of the proteins involved in thyroid hormonogenesis Of note, the role of NF-κB in thyroid physiology
was confirmed assessing TSH-induced gene expression in primary cultures of NEMO-deficient thyrocytes. Moreover, chromatin
immunoprecipitation and knock-down experiments revealed that p65 is a transcriptional effector of TSH actions inducing
the expression of genes involved in thyroid hormonogenesis. Altogether our results point to NF-κB as a pivotal mediator in the
TSH-induced thyroid follicular cell differentiation. Increasing evidence indicates that NF-κB participates in the pathogenesis
of autoimmune diseases, being a key factor in the interface between inflammation and cancer. We speculate that a misbalance
in TSH signaling regulation could have potential implication in thyroid pathophysiology through the modulation of NF-κB
signaling.
