Polyomavirus-induced malignant transformation: comparative analysis of wild type and mutant middle T-overexpressing...

Polyomavirus, a DNA tumor virus, expresses three viral oncoproteins (large, middle and small T antigens), causes malignant transformation in cell culture and induces multiple tumors in vivo. The middle T (MT) antigen seems to play an essential role in transformation and tumorigenicity. The observation that MT-overexpressing cell lines are able to grow in the absence of PDGF (platelet-derived growth factor) led several laboratories to study the mechanism underlying MT-induced growth deregulation and the signal transduction pathway used by this viral oncoprotein. A number of cellular proteins were shown to be common to both the normal PDGF mitogenic pathway and the MT transforming pathway. The expression of some PDGF primary response genes (fos, jun, myc, JE, KC) was shown to be rendered constitutive by MT overexpression. Using MT mutants, important domains for binding and activation of cytoplasmic proteins were mapped. Wild type and mutant MT cell lines are used in our laboratory to analyze the expression and activity of the PDGF early response genes during cell transformation and correlate them with activation of specific cytoplasmic proteins. In addition to abrogating the PDGF requirement for growth, activation of cellular proteins caused by MT results in cell lines that have an altered morphology and are able to form colonies in agarose. These changes may be due to alterations in connexin 43 and other cell surface proteins.