| Research Abstract |
In the current study, we focused on the ET-1-activated signal transduction pathways in cancer cells and found that ET-1, via activation of ETB receptors, induced expression of p53 and apoptotic cell death of A375 melanoma cells. There was a threshold value of ETB receptor densities expressed by individual cells to induce these responses and the receptor densities were controlled by a cell-cycle-dependent manner. We also found that ET-1/ETA complexes can be internalized both via clathrin-coated pits and caveolae and that the pathway selection was controlled by cholesterol contents of the plasma membrane. In relation to the latter finding, we analyzed the function of Niemann-Pick C1 protein that plays a critical role in the maintenance of cellular cholesterol homeostasis. We found that in addition to its critical role in cholesterol outflow from the late endosome, NPC1 protein is involved in the transport of GM1 ganglioside from the early endosome to the plasma membrane. This finding suggested that the internalization of ET-1/ETA complexes could be controlled by NPC1 in an indirect manner. Thus, the current study gave new insights both to the ET-1-induced signal transduction and the internalization mechanism of ET-1/receptor complexes.
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