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Thomas L. Benjamin, PhD

Virginia and D.K. Ludwig Professor of Microbiology and Immunobiology, Emeritus, Department of Emeritus, Harvard Medical School

Contact Info

Thomas Benjamin
Harvard Medical School
Harvard Medical School, NRB

Boston, MA, 02115
Mailstop: Benjamin Lab, Room 939i
Phone: 617-432-1960
Fax: 617-432-2689
thomas_benjamin@hms.harvard.edu

Assistant

Not Available.

DF/HCC Program Affiliation

Cancer Genetics

Research Abstract

As a Visiting Professor in Dr. Carl Novina's Lab, I have been investigating the basic biology and tumor suppressor functions of SALL2.The SALL2 protein (p150) is a target of the polyoma large T antigen. p150 is a DNA binding transcription factor with growth arrest and proapoptotic properties similar to p53. Unlike p53, p150 is not frequently mutated in human cancers. A possible explanation for this observation is promoter silencing by DNA methylation as shown in ovarian carcinomas. Together with Drs. Novina and Drapkin, we are exploring the fundamental biology of p150 and ways of demethylating the SALL2 promoter in ovarian cancers.

The highly oncogenic mouse polyomavirus is amenable to study both in cell culture and in its natural host. This system thus provides opportunities to study genetic determinants of virus and host as they effect tumor development in a variety of tissues.

Viral Determinants - The virus is armed with proto-oncogene activation functions through interaction of the middle T protein with pp60c-src and subsequent activation of Shc-ras-raf-MAPK, P13-K, and PL-Cg pathways, and also with tumor suppressor gene inactivation functions through binding of p110Rb by the large T protein. [Interestingly, polyoma has not been shown to interact with p53.] Effects of mutations of discrete viral functions on tumor induction are not always predictable based on results in cell culture system. For example, pRb binding mutants are unable to replicate in or to promote immortalization of primary cells in vitro but replicate and induce tumors well in the mouse; middle T mutants that are defective in transforming established fibroblasts can still induce a broad array of tumors, but with changes in the tissue spectrum and histological properties of the tumors. Differences in growth control networks operating in different target cell types must affect the response to the virus and the likelihood of undergoing neoplastic transformation.

Host Determinants - Responses to polyoma vary greatly among inbred mouse strains. The ability to mount an effective anti-tumor immune response is a major determinant of resistance. This ability is linked to MHC type and can be overcome by irradiation or other immunosuppressive treatments. Susceptible mice have mechanisms that actively override or prevent anti-tumor immune responses. Highly susceptible standard inbred strains are all of the H2k haplotype. These strains also express an endogenous mouse mammary tumor virus superantigen that effectively deletes essential precursors of polyoma specific cytotoxic T lymphocytes (CTLs). Some recently derived 'wild' mouse inbred strains show a different form of susceptibility that is based not on endogenous superantigen but rather on an inability to generate virus-specific CTLs from available precursors.
A non-immunological form of resistance has also been documented. This is based on the observation that mice of certain strains fail to develop tumors even if irradiated prior to virus inoculation. The radiation-resistant form of host resistance targets the virus directly and blocks its dissemination by an unknown mechanism. The host genetic background can also affect tumor development or behavior in a tissue-specific manner. Mus. spretus, for example, shows strong resistance to development of mammary tumors but develops all the other major tumor types. Polyoma tumors are generally not highly metastatic; however, in one of the 'wild' inbred strains primary bone tumors metastasize regularly to both lung and liver.

Publications

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