SV40 and Notch-I: multi-functionality meets pleiotropy.

Abstract

We have discovered that Simian virus 40 (SV40) infection of human mesothelial cells induces Notch-1. Upregulation of Notch-1 is achieved at the transcriptional level and requires the activity of both the large (90-100 kDa) and the small (20 kDa) SV40 tumor antigens. Notch-1 upregulation is maintained in SV40-transformed mesothelial cell lines in tissue culture, and Notch-1 is overexpressed only in SV40-positive mesotheliomas. Chemical inactivation of Notch-1 causes cell growth arrest of SV40-transformed human mesothelial cells. Our findings indicate that Notch-1 activation plays an important role in SV40-mediated carcinogenesis. Notch-1 is a pleiotropic gene that influences cell differentiation, proliferation and apoptosis. The effects of Notch-1 activation are species and cell type specific, in that, in different species or cell type within the same species, Notch-1 signaling can cause opposite effects. In this chapter, we review some general aspects of Notch signaling, and how Notch signaling regulates differentiation, the cell cycle and apoptosis. Recent data involving Notch and human cancer will be discussed. Then, we will deal with the current information regarding a specific form of lung cancer (malignant mesothelioma) and the involvement of SV40 in the pathogenesis of this form of human cancer. We will enter into the details of SV40-mediated cell transformation, and the specific interaction between SV40 and primary human mesothelial cells when infected with SV40 in vitro.