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Journal of Virology, April 2005, p. 4180-4190, Vol. 79, No. 7
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.7.4180-4190.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Activation of CREB/ATF Sites by Polyomavirus Large T Antigen

Tara M. Love,1 Rowena de Jesus,1 Jennifer A. Kean,1 Qing Sheng,2 Andrew Leger,1 and Brian Schaffhausen1*

Department of Biochemistry, Tufts University School of Medicine,1 Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts2

Received 27 August 2004/ Accepted 5 November 2004

Polyomavirus large T antigen (LT) has a direct role in viral replication and a profound effect on cell phenotype. It promotes cell cycle progression, immortalizes primary cells, blocks differentiation, and causes apoptosis. While much of large T function is related to its effects on tumor suppressors of the retinoblastoma susceptibility (Rb) gene family, we have previously shown that activation of the cyclin A promoter can occur through a non-Rb-dependent mechanism. Here we show that activation occurs via an ATF/CREB site. Investigation of the mechanism indicates that large T can synergize with CREB family members to activate transcription. Experiments with Gal4-CREB constructs show that synergy is independent of CREB phosphorylation by protein kinase A. Examination of synergy with Gal4-CREB deletion constructs indicates that large T acts on the constitutive activation domain of CREB. Large T can bind to CREB in vivo. Genetic analysis shows that the DNA-binding domain (residues 264 to 420) is sufficient to activate transcription when it is localized to the nucleus. Further analysis of the DNA-binding domain shows that while site-specific DNA binding is not required, non-site-specific DNA binding is important for the activation. Thus, CREB binding and DNA binding are both important for large T activation of CREB/ATF sites. In contrast to previous models where large T transactivation occurred indirectly, these results also suggest that large T can act directly at promoters to activate transcription.

* Corresponding author. Mailing address: Department of Biochemistry, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. Phone: (617) 636-6876. Fax: (617) 636-2409. E-mail: brian.schaffhausen{at}tufts.edu.

Journal of Virology, April 2005, p. 4180-4190, Vol. 79, No. 7
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.7.4180-4190.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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