Thymidine kinase, DNA synthesis and cancer

Abstract

A resume has been presented of some recent investigations which show that DNA synthesis can be initiated in many types of quiescent animal cells by external stimuli, by introducing a quiescent nucleus into the cytoplasm of a proliferating cell, or by a virus infection. The components of the DNA replication apparatus are described. It is shown that deoxyribonucleoside triphosphate pools increase substantially in animal cells at the time DNA synthesis is initiated due to the enhanced activities of enzymes functioning in nucleotide synthesis. Especially striking is the increase of thymidine kinase activity, indicating that this enzyme may be a useful marker of the shift from the quiescent to the replicative state. The thymidine kinase isozymes of vertebrate cells have been characterized. Thymidine kinase F, which is found principally in the cytosol, is the isozyme that increases when G1 (Go) phase cells are stimulated or infected with oncogenic viruses. Chick cytosol thymidine kinase F can also be reactivated by introducing differentiated chick erythrocyte nuclei into the cytoplasm of enzyme-deficient LM (TK-) mouse cells. Furthermore, herpesviruses code for distinctive, virus-specific thymidine kinase isozymes, so that another way to transform thymidine kinase-deficient LM TK-) cells to kinase-positive cells is by infecting them with UV-irradiated herpes simplex viruses. The experiments on the activation of DNA synthesis and thymidine kinase F activity have been discussed in the context of the proliferative activity in vivo and the immortalization in culture of neoplastic cells. These experiments suggest that genes determining cell cycle proteins are readily accessible to transcription and translation in essentially all nucleated cells. The tendency of transformed cells to become multinucleated after cytochaliasin B treatment also suggests that one important difference between malignant cells and most normal cells may be the ability of malignant cells to 'stockpile' the proteins (and/or their messenger RNAs) of the DNA replicative apparatus and to maintain the 'stockpiles' in progeny cells.