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Journal of Virology, August 2006, p. 7295-7307, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.00679-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Independent Contributions of Polyomavirus Middle T and Small T to the Regulation of Early and Late Gene Expression and DNA Replication

Li Chen,{dagger} Xiaoyu Wang,{dagger} and Michele M. Fluck*

Department of Microbiology and Molecular Genetics, Interdepartmental Program in Cell and Molecular Biology, Michigan State University, East Lansing, Michigan 48824-1101

Received 4 April 2006/ Accepted 12 May 2006

We previously showed that murine polyomavirus mutants that lack both middle T (MT) and small T (ST) functions have a severe pleiotropic defect in early and late viral gene expression as well as genome amplification. The respective contribution of MT and ST to this phenotype was unclear. This work separates the roles of MT and ST in both permissive mouse cells and nonpermissive rat cells. It demonstrates for the first time a role for both proteins. To gain insight into the signaling pathways that might be required, we focused on MT and its mutants. The results show that each of the major MT signaling connections, Shc, phosphatidylinositol 3'-kinase, and phospholipase C {gamma}1, could contribute in an additive way. Unexpectedly, a mutant lacking all these connections because the three major tyrosines had been converted to phenylalanine retained some activity. A mutant in which all six MT C-terminal tyrosines had been mutated was inactive. This suggests a novel signaling pathway for MT that uses the minor tyrosines. What is common to ST and the individual MT signaling pathways is the ability to signal to the polyomavirus enhancer, in particular to the crucial AP-1 and PEA3/ets binding sites. This connection explains the pleiotropy of MT and ST effects on transcription and DNA replication.

* Corresponding author. Mailing address: Department of Microbiology and Molecular Genetics, Interdepartmental Program in Cell and Molecular Biology, Michigan State University, East Lansing, MI 48824-1101. Phone: (517) 355-6463, ext. 1540. Fax: (517) 353-8957. E-mail: fluck{at}msu.edu.

{dagger} L.C. and X.W. contributed equally to this work.

Journal of Virology, August 2006, p. 7295-7307, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.00679-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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