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Journal of Virology, November 2004, p. 11962-11971, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.11962-11971.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Identification of a Negative Regulatory Element in the Epstein-Barr Virus Zta Transactivation Domain That Is Regulated by the Cell Cycle Control Factors c-Myc and E2F1

Zhen Lin, Qinyan Yin, and Erik Flemington*

Department of Pathology and Molecular and Cellular Biology Graduate Program, Tulane Health Sciences Center and Tulane Cancer Center, New Orleans, Lousiana

Received 7 April 2004/ Accepted 21 June 2004

Reactivation in Epstein-Barr virus (EBV) is closely associated with a G0/G1 cell cycle arrest which can be induced either by lytic cycle-inducing agents or by the immediate-early gene product Zta. Accumulating evidence shows that in epithelial cells, downregulation of the proto-oncogene, c-myc, plays an important role in lytic cycle-associated cell growth arrest. Here, we provide evidence that c-Myc provides a gatekeeper function to ensure that certain cell cycle inhibitory events have been capitulated prior to full progression into the lytic cycle. Specifically, we show that reconstitution of c-Myc expression during the lytic cycle to levels observed in cycling uninduced cells inhibits the transactivation function of Zta. Nuclear localization studies show that c-Myc does not grossly alter the nuclear localization of Zta or its association with the insoluble nuclear fraction. Enforced expression of another transcription factor that promotes cell cycle progression, E2F1, also inhibits Zta transactivation. Analysis of c-Myc- and E2F1-mediated inhibition of a panel of Zta mutants shows parallel genetics and inhibition maps to a small bipartite sequence located between amino acids 29 and 53 of Zta, containing homology to the proline-rich domain of the tumor suppressor protein p53. Mutation of a conserved tryptophan residue located at amino acid 49 of Zta largely prevents inhibition by both c-Myc and E2F1. These studies identify a negative regulatory element within the Zta activation domain that is regulated by the cell cycle-promoting factors c-Myc and E2F1.

* Corresponding author. Mailing address: Department of Pathology, SL79, 1430 Tulane Ave., New Orleans, LA 70112. Phone: (504) 988-1167. Fax: (504) 588-5516. E-mail: eflemin{at}tulane.edu.

Journal of Virology, November 2004, p. 11962-11971, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.11962-11971.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Huang, J., Liao, G., Chen, H., Wu, F. Y., Hutt-Fletcher, L., Hayward, G. S., Hayward, S. D. (2006). Contribution of C/EBP Proteins to Epstein-Barr Virus Lytic Gene Expression and Replication in Epithelial Cells. J. Virol. 80: 1098-1109 [Abstract] [Full Text]  


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