We have previously reported that gelsolin, an actin binding protein, regulates the fibrillization of amyloid-beta protein. We report here that the expression of cytoplasmic gelsolin (cgelsolin) was upregulated in a concentration-dependent manner when SH-SY5Y, PC-12, and HEK-293 cells were subjected to oxidative stress by treatment with hydrogen peroxide (H(2)O(2). Further studies were done to elucidate the mechanism involved in the regulation of c-gelsolin expression in cells. Pretreatment of cells with cycloheximide (an inhibitor of protein synthesis) resulted in significant inhibition of H(2)O(2)induced c-gelsolin expression, suggesting the possible de novo synthesis of c-gelsolin in cells. Staurosporine, a potent inhibitor of a variety of protein kinases including protein kinase C (PKC), also blocked the H(2)O(2)induced expression of cgelsolin. However, both H(2)O(2) and staurosporine activated the mitogen-activated protein kinases (MAPKs), i.e., c-Jun N-terminal kinase, P38, and extracellular signal-regulated kinase. Pretreatment of cells with Calphostin C, an inhibitor of PKC, blocked the upregulation of cgelsolin induced by H(2)O(2), while specific inhibitors of MAPKs had no effect on c-gelsolin expression, suggesting that MAPKs may not be involved in H(2)O(2)mediated upregulation of cgelsolin. On the other hand, phorbol-12-myristate-13-acetate, an activator of PKC, induced the expression of c-gelsolin. Our studies indicate that c-gelsolin is upregulated in cells under oxidative stress, and PKC is involved in its upregulation. It is suggested that activators of PKC that induce gelsolin expression may have therapeutic significance in Alzheimer's disease.