3. Raj GV, Khalili K (1995) Transcriptional regulation: lessons from the human neurotropic polyomavirus, JCV. Virology 213: 283–291. 4. Suzuki S, Sawa H, Komagome R, Orba Y, Yamada M, et al. (2001) Broad distribution of the JC virus receptor contrasts with a marked cellular restriction of virus replication. Virology 286: 100–112. 5. Frisque RJ, Hofstetter C, Tyagarajan SK (2006) Transforming activities of JC virus early proteins. Adv Exp Med Biol 577: 288–309. 6. Ravichandran V, Major EO (2006) Viral proteomics: a promising approach for understanding JC virus tropism. Proteomics 6: 5628–5636. 7. Bollag B, Prins C, Snyder EL, Frisque RJ (2000) Purified JC virus T and T’ proteins differentially interact with the retinoblastoma family of tumor suppressor proteins. Virology 274: 165–178. 8. Bollag B, Kilpatrick LH, Tyagarajan SK, Tevethia MJ, Frisque RJ (2006) JC virus T’135, T’136 and T’165 proteins interact with cellular p107 and p130 in vivo and influence viral transformation potential. J Neurovirol 12: 428–442. 9. Cheng J, DeCaprio J, Fluck MM, Schaffhausen BS (2009) Cellular transforma- tion by simian virus 40 and murine polyoma virus T antigens. Sem Cancer Biol 19: 218–228. 10. Yu Y, Alwine JC (2008) Interaction between simian virus 40 large T antigen and insulin receptor substrate 1 is disrupted by the K1 mutation, resulting in the loss of large T antigen-mediated phosphorylation of Akt. J Virol 82: 4521–4526. 11. Peden KW, Srinivasan A, Farber JM, Pipas JM (1989) Mutants with changes within or near a hydrophobic region of simian virus 40 large tumor antigen are defective for binding cellular protein p53. Virology 168: 13–21. 12. Poulin DL, Kung AL, DeCaprio JA (2004) p53 targets simian virus 40 large T antigen for acetylation by CBP. J Virol 78: 8245–8253. 13. Borger DR, DeCaprio JA (2006) Targeting of p300/CREB binding protein coactivators by simian virus 40 is mediated through p53. J Virol 80: 4292–4303. 14. Shimazu T, Komatsu Y, Nakayama KI, Fukazawa H, Horinouchi S, et al. (2006) Regulation of SV40 large T-antigen stability by reversible acetylation. Oncogene 25: 7391–7400. 15. Gan DD, Khalili K (2004) Interaction between JCV large T-antigen and beta- catenin. Oncogene 23: 483–490. 16. Campbell KS, Mullane KP, Aksoy IA, Stubdal H, Zalvide J, et al. (1997) DnaJ/ hsp40 chaperone domain of SV40 large T antigen promotes efficient viral DNA replication. Genes Dev 11: 1098–1110. 17. Saenz-Robles MT, Sullivan CS, Pipas JM (2001) Transforming functions of simian virus 40. Oncogene 20: 7899–7907. 18. Yu J, Boyapati A, Rundell K (2001) Critical role for SV40 small-t antigen in human cell transformation. Virology 290: 192–198. 19. Chang LS, Pan S, Pater MM, Di Mayorca G (1985) Differential requirement for SV40 early genes in immortalization and transformation of primary rat and human embryonic cells. Virology 146: 246–261. 20. Cicala C, Avantaggiati ML, Graessmann A, Rundell K, Levine AS, et al. (1994) Simian virus 40 small-t antigen stimulates viral DNA replication in permissive monkey cells. J Virol 68: 3138–3144. 21. Cegielska A, Shaffer S, Derua R, Goris J, Virshup DM (1994) Different oligomeric forms of protein phosphatase 2A activate and inhibit simian virus 40 DNA replication. Mol Cell Biol 14: 4616–4623. 22. Fahrbach KM, Katzman RB, Rundell K (2008) Role of SV40 ST antigen in the persistent infection of mesothelial cells. Virology 370: 255–263. 23. Mungre S, Enderle K, Turk B, Porras A, Wu YQ, et al. (1994) Mutations which affect the inhibition of protein phosphatase 2A by simian virus 40 small-t antigen in vitro decrease viral transformation. J Virol 68: 1675–1681. 24. Campbell KS, Auger KR, Hemmings BA, Roberts TM, Pallas DC (1995) Identification of regions in polyomavirus middle T and small t antigens important for association with protein phosphatase 2A. J Virol 69: 3721–3728. 25. Mateer SC, Fedorov SA, Mumby MC (1998) Identification of structural elements involved in the interaction of simian virus 40 small tumor antigen with protein phosphatase 2A. J Biol Chem 273: 35339–35346. 26. Sontag E (2001) Protein phosphatase 2A: the Trojan Horse of cellular signaling. Cellular Signal 13: 7–13. 27. Zhao Y, Boguslawski G, Zitomer RS, DePaoli-Roach AA (1997) Saccharomyces cerevisiae homologs of mammalian B and B’ subunits of protein phosphatase 2A direct the enzyme to distinct cellular functions. J Biol Chem 272: 8256–8262. 28. Walter G, Ferre F, Espiritu O, Carbone-Wiley A (1989) Molecular cloning and sequence of cDNA encoding polyoma medium tumor antigen-associated 61-kDa protein. Proc Natl Acad Sci U S A 86: 8669–8672. 29. Pallas DC, Shahrik LK, Martin BL, Jaspers S, Miller TB, et al. (1990) Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A. Cell 60: 167–176. 30. Nunbhakdi-Craig V, Craig L, Machleidt T, Sontag E (2003) Simian virus 40 small tumor antigen induces deregulation of the actin cytoskeleton and tight junctions in kidney epithelial cells. J Virol 77: 2807–2818. 31. Sontag E, Fedorov S, Kamibayashi C, Robbins D, Cobb M, et al. (1993) The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the map kinase pathway and induces cell proliferation. Cell 75: 887–897. 32. Sablina AA, Hahn WC (2008) SV40 small T antigen and PP2A phosphatase in cell transformation. Cancer Metastasis Rev 27: 137–146. 33. Yuan H, Veldman T, Rundell K, Schlegel R (2002) Simian virus 40 small tumor antigen activates AKT and telomerase and induces anchorage-independent growth of human epithelial cells. J Virol 76: 10685–10691. JCV Small t Protein Functions 34. Andrabi S, Gjoerup OV, Kean JA, Roberts TM, Schaffhausen B (2007) Protein phosphatase 2A regulates life and death decisions via Akt in a context-dependent manner. Proc Natl Acad Sci U S A 104: 19011–19016. 35. Bollag B, Chuke W-F, Frisque RJ (1989) Hybrid genomes of the polyomaviruses JC virus, BK virus, and simian virus 40: identification of sequences important for efficient transformation. J Virol 63: 863–872. 36. Tevethia SS, Epler M, Georgoff I, Teresky A, Marlow M, et al. (1992) Antibody response to human papovavirus JC (JCV) and simian virus 40 (SV40) T antigens in SV40 T antigen-transgenic mice. Virology 190: 459–464. 37. Sompayrac LM, Danna KJ (1981) Efficient infection of monkey cells with DNA of simian virus 40. Proc Natl Acad Sci U S A 78: 7575–7578. 38. Lynch KJ, Frisque RJ (1990) Identification of critical elements within the JC virus DNA replication origin. J Virol 64: 5812–5822. 39. Hirt B (1967) Selective extraction of polyoma DNA from infected mouse cell cultures. J Mol Biol 26: 365–369. 40. Sariyer IK, Khalili K, Safak M (2008) Dephosphorylation of JC virus agnoprotein by protein phosphatase 2A: inhibition by small t antigen. Virology 375: 464–479. 41. Jog P, Joshi B, Dhamankar V, Imperiale MJ, Rutila J, et al. (1990) Mutational analysis of simian virus 40 small-t antigen. J Virol 64: 2895–2900. 42. Li JJ, Kelly TJ (1985) Simian virus 40 DNA replication in vitro: specificity of initiation and evidence for bidirectional replication. Mol Cell Biol 5: 1238–1246. 43. Topp WC (1980) Variable defectiveness for lytic growth of the dl 54/59 mutants of simian virus 40. J Virol 33: 1208–1210. 44. Nesper J, Smith RWP, Kautz AR, Sock E, Wegner M, et al. (1997) A cell-free replication system for human polyomavirus JC DNA. J Virol 71: 7421–7428. 45. Prins CF, Frisque RJ (2001) JC virus T’ proteins encoded by alternatively spliced early mRNAs enhance T antigen-mediated viral DNA replication in human cells. J Neurovirol 7: 250–264. 46. Peden KW, Pipas JM, Pearson-White S, Nathans D (1980) Isolation of mutants of an animal virus in bacteria. Science 209: 1392–1396. 47. Chuke W-F, Walker DL, Peitzman LB, Frisque RJ (1986) Construction and characterization of hybrid polyomavirus genomes. J Virol 60: 960–971. 48. Haggerty S, Walker DL, Frisque RJ (1989) JC virus-simian virus 40 genomes containing heterologous regulatory signals and chimeric early regions: identification of regions restricting transformation by JC virus. J Virol 63: 2180–2190. 49. Lynch KJ, Haggerty S, Frisque RJ (1994) DNA replication of chimeric JC virus- simian virus 40 genomes. Virology 204: 819–822. 50. Tavis JE, Trowbridge PW, Frisque RJ (1994) Converting the JCV T antigen Rb binding domain to that of SV40 does not eliminate viral viability. Virology 199: 384–392. 51. Sontag E, Sontag JM, Garcia A (1997) Protein phosphatase 2A is a critical regulator of protein kinase C zeta signaling targeted by SV40 small t to promote cell growth and NF-kappaB activation. EMBO J 16: 5662–5671. 52. Sontag JM, Sontag E (2006) Regulation of cell adhesion by PP2A and SV40 small tumor antigen: an important link to cell transformation. Cell Mol Life Sci 63: 2979–2991. 53. Chen Y, Xu Y, Bao Q, Xing Y, Li Z, et al. (2007) Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40. Nat Struct Mol Biol 14: 527–534. 54. Cho US, Morrone S, Sablina AA, Arroyo JD, Hahn WC, et al. (2007) Structural basis of PP2A inhibition by small t antigen. PLoS Biol 5: e202. 55. Sullivan CS, Pipas JM (2002) T antigens of simian virus 40: molecular chaperones for viral replication and tumorigenesis. Micro Mol Biol Rev 66: 179–202. 56. Ruediger R, Brewis N, Ohst K, Walter G (1997) Increasing the ratio of PP2A core enzyme to holoenzyme inhibits Tat-stimulated HIV-1 transcription and virus production. Virology 238: 432–443. 57. Yang SI, Lickteig RL, Estes R, Rundell K, Walter G, et al. (1991) Control of protein phosphatase 2A by simian virus 40 small-t antigen. Mol Cell Biol 11: 1988–1995. 58. Lee C, Cho Y (2002) Interactions of SV40 T antigen and other viral proteins with retinoblastoma tumor suppressor. Rev Med Virol 12: 81–92. 59. Chemes LB, Sanchez IE, Smal C, de Prat-Gay G (2010) Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein. FEBS J 277: 973–988. 60. Pan W, Cox S, Hoess RH, Grafstrom RH (2002) A cyclin D1/cyclin-dependent kinase 4 binding site within the C domain of the retinoblastoma protein. Cancer Res 61: 2885–2891. 61. Swenson JJ, Frisque RJ (1995) Biochemical characterization and localization of JC virus large T antigen phosphorylation domains. Virology 212: 295–308. 62. Tyagarajan SK, Frisque RJ (2006) Stability and function of JC virus large T antigen and T’ proteins are altered by mutation of their phosphorylated threonine 125 residues. J Virol 80: 2083–2091. 63. Virshup DM, Kauffman MG, Kelly TJ (1989) Activation of SV40 DNA replication in vitro by cellular protein phosphatase 2A. EMBO J 8: 3891–3898. 64. Carbone M, Hauser J, Carty MP, Rundell K, Dixon K, et al. (1992) Simian virus 40 (SV40) small t antigen inhibits SV40 DNA replication in vitro. J Virol 66: 1804–1808. 65. Kwun HJ, Guastafierro A, Shuda M, Meinke G, Bohm A, et al. (2009) The minimum replication origin of Merkel cell polyomavirus has a unique large T- antigen loading architecture and requires small t-antigen expression for optimal replication. J Virol 83: 12118–12128. PLoS ONE | www.plosone.org 12 May 2010 | Volume 5 | Issue 5 | e10606