Affiliations: New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
Correspondence:
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Correspondence to: Ved Chauhan, Ph.D., New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. Tel.: +1 718 494 5257; Fax: +1 718 698 7916; E-mail: [email protected].
Abstract: We have previously reported that gelsolin, an actin binding protein, regulates the fibrillization of amyloid-β 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 (H2O2). 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 H2O2-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 H2O2-induced expression of cgelsolin. However, both H2O2 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 H2O2, while specific inhibitors of MAPKs had no effect on c-gelsolin expression, suggesting that MAPKs may not be involved in H2O2-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.
Keywords: Gelsolin, mitogen-activated protein kinases, oxidative stress, protein kinase C
