Fluck, Michele M.
University Distinguished Professor
B.S., 1964, University of Geneva, Switzerland
Ph.D., 1972, University of Geneva, Switzerland
Postdoctoral Fellow Assistant Professor, 1972-1979, Harvard Medical School
Department of Microbiology and Molecular Genetics
4197 Biomedical Physical Sciences
Michigan State University
East Lansing, MI 48824
Phone: (517) 884-5327
Work in our laboratory uses polyoma virus, a mouse tumor virus, as a model to study the interactions of a virus with its host cells. Two different approaches are used. One consists of describing the integration pathway of the viral genome into the host chromosome in the process of neoplastic transformation of established cell lines in tissue culture. We have demonstrated that the integration process involves interviral recombination. This recombination is very unusual because it occurs between viral genomes packaged as chromatin, because it occurs at a rate higher than that described for any other recombination system studied in mammalian cells, and because it only occurs among the viral genomes which become integrated. Thus, the viral genomes appear to interact with a highly recombinogenic center in the process of integration. We are interested in understanding what features of the host chromosome provide sites for the integration of the viral genomes (DNase I sensitivity, proximity to the chromosome scaffold, etc). For this purpose, integrated viral genomes and their flanking host sequences are cloned from genomic libraries. We are also attempting to localize the integrated viral sequences at the chromosome level, using in situ hybridization of metaphase chromosomes. We hope that these studies will provide some insight in the integration pathway of viral genomes, the mechanisms of recombination in mammalian cells, as well as in the structure of the host chromosome in interphase. In many, but not all tissues, gene expression varies in function of the age of the animal: for example expression decreases with age in the kidney, and increases in the spleen. Different subregions of the enhancer control replication in different tissues. We have followed in detail replication in the mammary gland, which is high at all times. When immunodeficient female mice are infected as adults, 100% of the mice develop rapid hyperplasia of the mammary gland followed by tumorigenesis.
The other approach consists of understanding viral pathogenesis at the animal level, using molecular techniques. In particular, the pattern of viral replication persistence and tumorigenesis in various tissues is analyzed by in situ hybridization of whole body sections of infected animals. We have found an important role for the viral enhancer in viral replication and persistence in the animal. The role of the immune response (specifically cytotoxic Tcells) in tumorigenesis is also examined.