Cellular location, differential regulation and function of selenoproteins in the human thryoid

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The normal human thyroid produces iodine-containing thyroid hormones by an H2O2-dependent peroxidase-catalyzed radicalic reaction, has a very high selenium content and expresses several selenocysteine-containing proteins. Severe selenium and iodine deficiencies lead to endemic cretinism and are risk factors for evolution of thyroid cancer. The first goal of this project is to characterize the expression and regulation of the secreted selenoprotein P (SeP) in thyroid tissue and thyroid cell lines. Further studies will address the issue whether SeP and the extracellular glutathione peroxidase isoenzyme (pGPx) participate in local antioxidative defense reactions and are secreted across the apical thyrocyte pole into the colloid space or across the basolateral membrane. Expression of selenoproteins in thyrocytes, stromal or vascular cells will be analyzed by in situ hybridization and immunohistochemistry. In thyrocytes, selenium-dependent molecular targets and functional endpoints will be identified for oxidative activation of the redox-sensitive transcription factor AP1, which controls proliferation and is involved in cell transformation. Interactions between thyrocytes and monocyte-derived cells will be studied under selenium deficiency and peroxidative stress conditions. We expect information on mechanisms and participation of selenoproteins in the evolution of goiter, cancer and thyroid autoimmune disease.