Medullary thyroid carcinomas in transgenic mice expressing a polyoma carboxyl-terminal truncated middle-T and wild type small-T antigens

Medullary thyroid carcinoma (MTC) is a rare human tumor affecting the calcitonin-secreting c-cells of the thyroid. Here me report that two independent strains of transgenic mice expressing a Polyomavirus (Py) truncated middle-T antigen (Delta MT), consisting of the aminoterminal 304 amino acids, and the full length Py small-T antigen, developed multifocal bilateral MTCs with 100% penetrance, Occasionally one strain also developed mammary and bone tumors. Furthermore, offspring from both transgenic lines displayed pronounced waviness of the whiskers and fur, previously associated,vith defective epidermal growth factor receptor signaling, Transgene transcription, driven by the homologous early promoter/enhancer, and the corresponding translation products mere detected in tumors and in many other organs which did not develop pathologies. The subcellular distribution of Delta MT and its interactions with the adapter proteins of the SHC family have also been analysed. Our study describes a novel murine model of MTC and provides evidence that the N-terminal 304 amino acid fragment of Py middle-T antigen, possibly in co-operation with small-T antigen, acts as a potent oncogene in c-cells of the thyroid.