DNA tumor viruses of the polyomavirus family have helped us understand important cellular processes, particularly those associated with the signal transduction of cell cycle regulation and transformation. For example, polyomavirus middle T antigen (PyMT) studies were crucial to the discovery of the importance of tyrosine phosphorylation (17) and phosphatidylinositol 3-kinase (PI3) kinase activity (70) in cellular signaling. Comparative studies of the individual members of the polyomavirus family have also been very informative. For example, p53 was discovered as a protein that associates with simian virus 40 (SV40) large T antigen (LT) (38, 39). Comparison of SV40 LT that binds p53 and transforms cells to polyomavirus LT (PyLT) that does neither of these focused attention on the role of p53 in cell cycle regulation.All members of the polyomavirus family produce a small T antigen (ST) as one of the early gene products. Polyomavirus small T antigen (POLST) and SV40 small T antigen (SVST) share many structural similarities with each other (Fig. 1). Both have an N-terminal J domain with a conserved HP DKGG motif that can bind heat shock proteins, and both possess zinc-binding cysteine motifs. Both POLST and SVST bind and perturb protein phosphatase 2A (PP2A) (51). PP2A functions as a trimeric ABC complex, where the scaffolding A subunit binds a catalytic subunit (C) and some regulatory B subunits (30). STs bind to the A and C subunit complexes (51, 64), displacing or preventing B subunits from binding. Since SVST binds to regions of the A subunit involved in B binding (12,14), the absence of B subunits in ST/PP2A complexes is not surprising.There is ample evidence suggesting that careful examination of ST is important. SVST contributes to the multioncoproteindirected transformation of human cells (24,59,76). Transgenic SVST contributes to mammary gland carcinogenesis (22). POLST complements MT for both transformation (4,45,49) and tumor induction (3). POLST effects on the cell cycle are well documented. POLST promotes cell cycle progression (46) and complements LT for S-phase induction (5, 51). Array analysis showed that SVST (43) and POLST (35) have large effects on cellular mRNA levels. SVST can transactivate (19,32,40,48,53,61,68) or repress (67) various promoters. POLST activates the fos (46) and myc (36) promoters. POLST is known to promote changes in viral chromatin structure that may underlie altered transcriptional activity (16). DNA viruses are very much concerned with issues of cell survival. It is therefore not surprising that both small Ts affect survival. Both POLST and SVST can be antiapoptotic. POLST can protect against serum starvation-induced apoptosis (2) and resists the effects of p53-induced apoptosis (54). SVST opposes apoptosis induced by LT (37) or CD95 (20). Both POLST (2) and SVST (21) can also be proapoptotic under some circumstances.Many ST functions are known to depend on their interactions with PP2A. Promotion of cell cycle by POLST (46), activation of promoters, such as myc (36), fos (4...