| Popis: |
Sodium iodide symporter (NIS) is a membrane glycoprotein that mediates iodide uptake into thyroid and several extra-thyroidal tissues. NIS is the basis for the post-operative use of radioiodide in detection and targeted ablation of differentiated thyroid cancer. However, NIS expression/function is reduced or absent in advanced thyroid cancer. NIS functional expression in non-targeted tissues contributes to adverse effects of radioiodide therapy. Further studies of the regulatory mechanisms of NIS expression/function are important to maximize the efficacy of radioiodide therapy and to extend the utility of exogenous NIS as an imaging reporter gene. Nasolacrimal duct obstruction is a complication associated with radioiodide therapy. NIS protein was detected in the columnar epithelial cells of normal lacrimal sac, but absent in lacrimal sacs from I131-treated patients, suggesting that active radioiodide uptake mediated by NIS may be responsible for radiation-induced injury of the lacrimal sac following radioiodide therapy. The extent of radioiodide uptake can vary among different cell types expressing exogenous NIS. Exogenous NIS proteins were targeted to cell surface in cell lines expressing various levels of exogenous NIS. In addition, a moderate increased in NIS protein levels markedly increased radioiodide uptake. Further increases in cell surface NIS levels did not translate into further increases in radioiodide uptake beyond a certain range, suggesting that NIS is not the sole factor dictating the extent of radioiodide uptake. MEK inhibition increased NIS protein levels in thyroid cells, yet decreased radioiodide uptake in cells expressing either endogenous or exogenous NIS. The possible effects of MEK inhibition on cell surface NIS levels, NIS binding affinity for I-, and iodide efflux were excluded. MEK inhibition decreased NIS velocity of iodide transport without decreasing NIS cell surface levels, suggesting that MEK inhibition decreased NIS activity at post-translational level. In vivo phosphorylation sites in NIS were identified by mass spectrometry analysis. Site-directed mutagenesis indicates that phosphorylation status of S43 and S581 appears to modulate velocity of iodide transport of NIS, whereas phosphorylation status of T577 may be important for NIS protein stability. Taken together, NIS protein levels/functional activity can be modulated by phosphorylation through distinct mechanisms. |
