fluck@msu.edu
        Phone: (517) 353-5014
        Home Department: Microbiology,
        Home Page Microbiology

University Distinguished Professor of Microbiology; Ph.D., 1972, University of Geneva, Switzerland; Postdoctoral Fellow, 1972-1979, Harvard Medical School.

        Work in my laboratory centers around understanding neoplastic transformation and oncogenesis by Polyomavirus (PyV), a small DNA tumor virus. This model system has two major advantages. PyV is a highly tumorigenic agent in its own host, the mouse, and infection induces very interesting tumors of the mammary gland. Secondly, since the viral genome encodes few proteins, the virus life cycle depends heavily upon cellular processes. Thus, the small DNA tumor viruses have provided invaluable tools to understand host processes, such as gene expression and DNA replication. Of particular interest at present, PyV and other members of its extended family, are the only viruses whose genomes are organized in a chromatin form.

        One of the PyV viral proteins, called middle T, is the viral oncogene. On its own, middle T is capable of transforming cells in tissue culture and of inducing tumors in mice. The middle T protein acts by activating a cellular tyrosine kinase-mediated signal transduction pathway. This pathway is similar to that activated by many growth factors and is disregulated in many human tumors. We are trying to understand the role of the viral oncogene in the life cycle of the virus, with the hope of getting new insights into transformation. We have recently discovered that middle T is in part responsible for the "out of control" mode of viral replication. This allows the viral genome to undergo many rounds of replication during a single S-phase, while host origins fire a single time. We are studying whether this deregulation is mediated by a middle T-controlled remodeling of the viral chromatin. We have also shown that, in contrast to the host, viral DNA replication proceeds through the G2 phase, permits mitosis, and continues through the all phases of the ensuing cell cycles.

        Another major project in the lab concerns the characterization of the mammary gland tumors that are induced following PyV infection. These tumors are ductal adenocarcinoma and very similar in histotype to the most common breast cancer tumors. We have recently shown that when we infect older mice and remove their ovaries following infection, the tumor growth rates are affected by the removal of ovarian hormones. This phenomenon resembles the estrogen-dependence observed in human breast tumors. We are trying to understand how estrogen may modulate
the growth of the PyV-induced tumors. In particular, we are asking whether estrogen and middle T effects converge into the same signal transduction pathway.

Selected Publications

Chen, M. C., D. Redenius, F. Ozati-Ashtiani, and M. M. Fluck. 1995. Enhancer-Mediated Role for Polyomavirus Middle T/Small T in DNA Replication. J. Virol. 69: 326-333.

Rondinelli, R. H., S. Z. Haslam, and M. M. Fluck. 1995. The Role of Ovarian Hormones, Age, and Mammary Gland Development in Polyomavirus Mammary Tumorigenesis. Oncogene 11: 1817-1827.

Fluck, M. M. and S. Z. Haslam. 1996. Mammary Tumors Induced by Polyomavirus. Breast Cancer Research and Treatment 39: 45-56.

Fluck, M. M. 1997. Tumor Studies with Polyomaviruses. In Encyclopedia of Cancer. Vol. III pp. 1926-1939. J. R. Bertino Ed., Academic Press, N.Y.

Wirth, J. J., L. G. Martin and M. M. Fluck. 1997. Oncogenesis of the Mammary Glands, Skin and Bones by Polyomavirus Correlates with Viral Persistence and Prolonged Genome Replication Potential. J. Virol. 71: 1072-1078.

Syu, L. J. and M. M. Fluck. 1997. Site Specific Amplification of the Integrated Polyomavirus Genome: A Case for a Context-Specific Overreplication Model of Gene Amplification. J. Mol. Biol. 271:76-99.

Wirth, J.J., L. Chen, and M. M. Fluck. 2000. Dissemination of Polyoma Capsid-Defective Genomes from Mammary Gland Tumors and Systemic Genome Increase. J. Mol. Biol. 74:6975-83.