Role of the amino-terminal domain of simian virus 40 early region in inducing tumors in secretin-expressing cells in transgenic mice

Background & Aims: The early region of simian virus 40 (SV40) encodes 2 tra nsforming proteins, large T (Tag) and small t antigen, that produce neuroen docrine tumors in the intestine and the pancreas when expressed in secretin cells of transgenic mice. Methods: Two SV40 early-region transgenes contai ning a deletion that eliminated expression of the small t antigen were expr essed in transgenic mice under control of the secretin gene. The 2 lines of mice, one expressing the native large T antigen and the other T antigen wi th a mutation in its N-terminal J domain, were examined to determine which biological activities of the SV40 early region were required for tumorigene sis. Results: Most animals expressing wild-type large T antigen developed p ancreatic insulinomas and lymphomas and died between 3 and 6 months of age. However, small intestinal neoplasms were extremely rare in the absence of small t antigen expression. Transgenic lines expressing the J domain mutant failed to develop tumors. Conclusions: Transformation of secretin-producin g enteroendocrine cells by SV40 requires functional cooperation between int act large T and small t oncoproteins. In contrast, large T antigen alone is sufficient to induce tumors in the endocrine pancreas and thymus.