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

The parvoviruses exert antiproliferative effects on transformed cells in culture. 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 proteins we have developed a human 293 cell line that expresses the adeno-associated virus (AAV) rep gene upon induction with heavy metal salts. When induced with both Zn(2+) and Cd(2+), Rep protein expression correlates with a cell cycle block in S phase (Yang, Q., Chen, F., and Trempe, J. P. (1994). J. Virology 68,7169-7177). However when induced with Cd(2+) alone, the Rep proteins are expressed and the cells are killed. Production of a nucleosomal DNA repeat pattern and degradation of poly-ADP ribose polymerase (PARP) suggest that killing occurs by apoptosis. These results demonstrate that AAV Rep protein expression in chemically stressed cells is cytotoxic due to induction of apoptotic pathways. Copyright 1999 Academic Press.