Disruption of c-Fos leads to increased expression of NAD(P)H : quinone oxidoreductase1 and glutathione S-transferase

Regulation of the basal and induced expression of detoxifying enzymes such as NAD(P)H:quinone oxidoreductase1 (NQO1) and glutathione S-transferase (GS T) by the antioxidant response element (ARE) is important for cellular prot ection against oxidative stress. The ARE contains AP1 and AP1-like elements and is known to bind to several leucine zipper proteins including c-Fos, P revious studies (Venugopal, R., and Jaiswal, A.K. (1996) Proc. Natl. Acad. Sci. USA 93, 14960-14965) have shown that overexpression of c-Fos in transf ected cells leads to repression of ARE-mediated gene expression, In the pre sent report, we used c-Fos-/- mice and investigated the physiological (in v ivo) role of c-Fos in repression of the NQO1 and GST genes expression, The analysis of enzyme activity levels showed significant increases in NQO1 and GST activities in several tissues of c-Fos-/- mice, as compared with wild type (c-Fos+/+) mice. The increases in enzyme activities were supported by Western analysis of respective proteins, Western analyses showed significan t increases in the expression of NQO1 in kidney, liver and skin tissues of c-Fos-/- mice, as compared with wild type (c-Fos+/+) controls. Western anal yses also demonstrated an increased expression of the GST Ya gene in kidney and liver tissues of the c-Fos-/- mice, These results confirm a negative ( repressive) role for c-Fos in the expression of NQO1, GST Ya, and other det oxifying enzyme genes. (C) 1998 Academic Press.