Microbiology & Molecular Genetics
Harvey Ozer, Ph.D.
Regulation of Cellular Aging and Carcinogenesis
Normal mammalian cells can be propagated in cell culture for only a limited time, eventually ceasing to proliferate ("senescence"). This phenomenon is a model for the cellular basis of human aging. On the other hand, cancer cells grow continuously in culture (and in the animal) and have overcome senescence; that is, they are "immortal". Hence replicative senescence is a mechanism of protection against cancer. We have been studying human diploid fibroblasts (HF) to understand the mechanism of multi-step carcinogenesis ("transformation") of such cells in culture and its effect on cellular aging. We have found that introduction of genes from the DNA tumor virus SV40 allows us to identify two key steps in this process. The SV40-encoded T antigens induce several changes in growth properties in HF but additional changes in cellular gene(s) are required for immortalization. We have isolated a matched series of clonally derived SV40-transformed HF with pre-immortal and immortal growth phenotypes, permitting the direct test of hypotheses concerning biochemical and genetic bases for immortalization of human cells. We have also mapped a specific chromosome rearrangement on chromosome 6 in different cell lines which is directly associated with immortalization. We are currently examining candidate genes (designated SEN6) based on their known location at 6q27. Chromosome rearrangements is this region have also been reported in several types of human cancer, suggesting that SEN6 is also involved in their development as well.
- Harvey, B.P., Banga, S.S. and H.L. Ozer (2004) Regulation of Multifunctional Ca2+/Calmodulin-dependent Protein Kinase II by the PP2C Phosphatase PPM1F in Fibroblasts. J. Biological Chemistry, 279:24889-24898.
- Benanti, J.A., Williams D., Robinson, K.L., Ozer, H.L. and D.A. Galloway (2002) Induction of extracellular matrix-remodeling genes by the senescence associated protein APA-1. Mol. Cell. Biol. 22:7385-7397.
- Macera- Bloch, L., Houghton, J., Lenahan, M., Jha, K.K. and H.L. Ozer. (2001) Termination of lifespan of SV40-transformed human fibroblasts in crisis is due to apoptosis. J. Cellular Physiology 190:332-344.
- Jha, K.K., Banga, S., Palejwala, V. and Ozer, H.L. (1998) SV40-mediated immortalization. Exp. Cell Res. 245:1-7.
- Banga, S.S., Kim, S., Hubbard, K., Dasgupta, T., Jha, K.K., Patsalis, P., Hauptschein, R., Gamberi, B., Dalla-Favera, R., Kraemer, P. and H.L. Ozer (1997) SEN6, a locus for SV40-mediated immortalization of human cells, maps to 6q26-27. Oncogene, 14:313-321.