SIMIAN-VIRUS-40 LARGE-T ANTIGEN BINDS P53 IN HUMAN MESOTHELIOMAS

We found that simian virus 40 (SV40) induces mesotheliomas in hamsters (1) and that 60% of human mesotheliomas contain and express SV40 seque nces', results now confirmed by others [ref. 3-5, and presentations by D. Griffiths & R. Weiss, F. Galateau-SallE, and H.I.P. at ''Simian vi rus 40: A possible human polyoma virus,'' NIH workshop, 27-28 January 1997, Bethesda, MD (transcript available through SAG Corp., Washington , DC 20008)]. Mesothelioma(6-8), an aggressive malignancy resistant to therapy, originates from the serosal lining of the pleural, pericardi al and peritoneal cavities. The incidence of mesothelioma continues to increase worldwide because of exposure to crocidolite asbestos. Howev er, at least 20% of mesotheliomas in the United States are not associa ted with asbestos exposure, and only a minority of people exposed to h igh concentrations of asbestos develop mesothelioma(6-8). Thus, other carcinogens may induce mesothelioma in individuals not exposed to asbe stos, and/or may render particular individuals more susceptible to the carcinogenic effect of asbestos. We investigated whether the expressi on of the 5V40 large T-antigen (Tag) interferes with the normal expres sion of the tumor suppressor gene p53 in human mesotheliomas. We found that SV40 Tag retains its ability to bind and to inactivate p53, a ce llular protein that when normally expressed plays an important role in suppressing tumor growth and in inducing sensitivity to therapy. Our findings do not establish a cause-and-effect relation, but indicate th at the possibility that SV40 contributes to the development of human m esotheliomas should be carefully investigated.