EARLY RESPONSE GENE INDUCTION FOLLOWING DNA DAMAGE IN ASTROCYTOMA CELL-LINES

Early response genes (ERGs) are a group of genes with low or absent ex pression in quiescent cells that can be induced rapidly by a variety o f proliferation and differentiation stimuli. c-jun and c-fos are proto types for this group of genes. Recent evidence suggests that DNA damag ing agents such as cytotoxic drugs and ionizing radiation can elicit s trong ERG induction, suggesting that these genes may be involved in DN A damage repair and/or cell death. Paralleling this interest in drug-i nduced ERG expression is a growing body of evidence implicating ERG ex pression as important to the intrinsic function of the central nervous system. We therefore set out to explore the pattern of chemotherapeut ic drug- and radiation-induced c-jun and c-fos expression in neuroecto dermally (astrocytic) derived cell lines. We have demonstrated that va rious chemotherapeutic agents and ionizing radiation can induce c-jun in a time- and concentration-dependent manner. Furthermore, this induc tion can be prevented by pretreatment of the cells with agents that pr otect against DNA damage. Finally, we have demonstrated that c-fos and c-jun expression and induction are discoordinately regulated, reflect ing a difference in astrocytic cell lines compared to hemapoietic cell lines. The possible relevance of these observations to the clinical r esistance of astrocytic tumors to standard chemotherapy and radiation is discussed.