Induction of apoptosis by cadmium and the adeno-associated virus Rep proteins

The parvoviruses exert antiproliferative effects on transformed cells in cu lture. The development of cell lines that inducibly express the parvovirus nonstructural proteins have implicated these proteins in the limitation of cell growth. To study the host cell interactions of the nonstructural prote ins we have developed a human 293 cell line that expresses the adeno-associ ated virus (AAV) rep gene upon induction with heavy metal salts. When induc ed with both Zn2+ and Cd2+, Rep protein expression correlates with a cell c ycle block in S phase (Yang, Q., Chen, F., and Trempe, J. P. (1994). J. Vir ology 68,7169-7177). However when induced with Cd2+ alone, the Rep proteins are expressed and the cells are killed. Production of a nucleosomal DNA re peal pattern and degradation of poly-ADP ribose polymerase (PARP) suggest t hat killing occurs by apoptosis. These results demonstrate that AAV Rep pro tein expression in chemically stressed cells is cytotoxic due to induction of apoptotic pathways. (C) 1999 Academic Press.