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SUMMARY The small DNA tumor viruses have provided a very long-lived source of insights into many aspects of the life cycle of eukaryotic cells. In recent years, the emphasis has been on cancer-related signaling. Here we review murine polyomavirus middle T antigen, its mechanisms, and its downstream pathways of transformation. We concentrate on the MMTV-PyMT transgenic mouse, one of the most studied models of breast cancer, which permits the examination of in situ tumor progression from hyperplasia to metastasis.

Simian Virus 40 (SV40) and Mouse Polyoma Virus (PY) are small DNA tumor viruses that have been used extensively to study cellular transformation. The SV40 early region encodes three tumor antigens, Large T (LT), small T (ST) and 17KT that contribute to cellular transformation. While PY also encodes LT and ST, the unique Middle T (MT) generates most of the transforming activity. SV40 LT mediated transformation requires binding to the tumor suppressor proteins Rb and p53 in the nucleus and ST binding to the protein phosphatase PP2A in the cytoplasm. SV40 LT also binds to several additional cellular proteins including p300, CBP, Cul7, IRS1, Bub1, Nbs1 and Fbw7 that contribute to viral transformation. PY MT transformation is dependent binding to PP2A and the Src family protein tyrosine kinases (PTK) and assembly of a signaling complex on cell membranes that leads to transformation in a manner similar to Her2/neu. Phosphorylation of MT tyrosine residues activates key signaling molecules including Shc/Grb2, PI3K and PLCγ1. The unique contributions of SV40 LT and ST and PY MT to cellular transformation have provided significant insights into our understanding of tumor suppressors, oncogenes and the process of oncogenesis.

Polyoma virus mutants of four functionally distinct groups have been mapped by the marker rescue technique using restriction enzyme fragments of wild-type viral DNA. Nontransforming host-range mutants map in the proximal part of the early region of the viral genome. The (3, 4, *).Temperature-sensitive (ts) mutants fall into three complementation groups-an early group (ts-a) that is defective in the initiation of transformation, and two late groups that are unaffected in transformation (5). One. mutant, ts-3, fails to complement all other mutants, and is probably defective in a virion protein (6).Physiological properties of hr-t mutants set them clearly apart from all known temperature-sensitive mutant groups, but do not permit one to decide whether they are altered in an "early" or a "late" viral function. In productive infection they complement well with ts mutants of both early and late classes; they also complement with ts-a mutants for transformationtt.We have employed the physical mapping procedure, devised and applied to bacteriophage XX-174 by Hutchison and Egdell (7), in order to map hr-t and ts mutants of polyoma virus. This procedure has recently been applied to ts mutants of simian virus 40 (SV40) (8-10) and polyoma virus (11). Our results show that hr-t mutants map in the proximal part of the region of viral DNA that is transcribed early during productive infection and in transformed cells. Alterations within the same small segment

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