Role of the Keap1/Nrf2 signaling pathway in the integration of the antioxidant response, the ubiquitin-proteasome system, and the endoplasmic reticulum stress response in thyroid land proteostasis

• Research unit: COST
• Project number: C15.0045

Key words (English)

antioxidant; ubiquitin; proteasome; Nrf2; Keap1; CHOP; thyroglobuline; iodine; iodide; thyroid; hyperthyroidism;hypothyroidism; goiter

Research programs (English)

COST-Action BM1307 - European network to integrate research on intracellular proteolysis pathways in health and disease

Short description (English)

There is substantial evidence that the Keap1/Nrf2 antioxidant response pathway cross-talks with the UPS and the UPR proteostasis systems in various tissues, yet there are very few studies on the existence and potential physiological importance of this interaction in the thyroid. In our studies we have shown that an established animal model of iodine overloa d is suitable for further investigations of this cross-talk in thyroid physiology; we have also assembled a collection of thyroid cancer samples that can be analyzed to the same end. Our preliminary data support the existence of a cross-talk between Nrf2 and the UPS/UPR and highlight potential underlying mechanisms that warrant further exploration. Thus, the present project will take advantage of our established experimental models to extend our research focus to the UPS and UPR proteostasis systems. The specific aims of the project are: Aim1: To characterize the impact of Keap1/Nrf2 signaling on the thyroid gland's UPS and UPR under basal conditions, under oxidative stress, and during aging. Aim2: To characterize the role of Nrf2 in the regulation of microRNA miR-122, a repressor of the UPR, in benign and transformed thyrocytes. Aim3: To characterize proteasome activity in different types of thyroid carcinoma (papillary, follicular, poorly differentiated, and anaplastic), and to correlate it with Keap1/Nrf2 pathway activity.

Further information (English)

Full name of research-institution/enterprise: Centre Hospitalier Universitaire Vaudois - CHUV Service d'Endocrinologie, Diabétologie et Métabolisme

Partners and International Organizations (English)

AT; BE; HR; CZ; DK; EE; FI; FR; DE; EL; HU; IS; IE; IL; IT; NL; NO; PL;PT; RO; RS;L Sl; ES; SE; TR; UK

Abstract (English)

There is substantial evidence that the Keap1/Nrf2 antioxidant response pathway cross-talks with the UPS and the UPR proteostasis systems in various tissues, yet there are very few studies on the existence and potential physiological importance of this interaction in the thyroid. In our studies we have shown that an established animal model of iodine overload is suitable for further investigations of this cross-talk in thyroid physiology; we have also assembled a collection of thyroid cancer samples that we are analyzing to the same end. Our preliminary data support the existence of a cross-talk between Nrf2 and the UPS/UPR and highlight potential underlying mechanisms that we are currently investigating in detail: In Aim1, we are characterizing the impact of Keap1/Nrf2 signaling on the thyroid gland's UPS and UPR under basal conditions, under oxidative stress, and during aging. In Aim2, we are characterizing the role of Nrf2 in the regulation of microRNA miR-122, a repressor of the UPR, in benign and transformed thyrocytes. In Aim3, we are characterizing proteasome activity in different types of thyroid carcinoma (papillary, follicular, poorly differentiated, and anaplastic), and we are examining its correlations with Keap1/Nrf2 pathway activity.

References in databases (English)

Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. [phone] Swiss Project-Number: C15.0045