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Journal of Virology, October 2006, p. 9951-9961, Vol. 80, No. 20
0022-538X/06/$08.00+0     doi:10.1128/JVI.01300-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Repression of HMGA2 Gene Expression by Human Cytomegalovirus Involves the IE2 86-Kilodalton Protein and Is Necessary for Efficient Viral Replication and Inhibition of Cyclin A Transcription

Mark Shlapobersky, Rebecca Sanders, Charles Clark, and Deborah H. Spector*

Department of Cellular and Molecular Medicine, Skaggs School of Pharmacy and Pharmaceutical Sciences, and Center for Molecular Genetics, University of California, San Diego, La Jolla, California 92093-0712

Received 20 June 2006/ Accepted 25 July 2006

Human cytomegalovirus (HCMV) infection results in dysregulation of several cell cycle genes, including inhibition of cyclin A transcription. In this work, we examine the effect of the HCMV infection on expression of the high-mobility group A2 (HMGA2) gene, which encodes an architectural transcription factor that is involved in cyclin A promoter activation. We find that expression of HMGA2 RNA is repressed in infected cells. To determine whether repression of HMGA2 is directly related to the inhibition of cyclin A expression and impacts on the progression of the infection, we constructed an HCMV recombinant that expressed HMGA2. In cells infected with the recombinant virus, cyclin A mRNA and protein are induced, and there is a significant delay in viral early gene expression and DNA replication. To determine the mechanism of HMGA2 repression, we used recombinant viruses that expressed either no IE1 72-kDa protein (CR208) or greatly reduced levels of IE2 86-kDa (IE2 86) protein (IE2 86{Delta}SX-EGFP). At a high multiplicity of infection, the IE1 deletion mutant is comparable to the wild type with respect to inhibition of HMGA2. In contrast, the IE2 86{Delta}SX-EGFP mutant does not significantly repress HMGA2 expression, suggesting that IE2 86 is involved in the regulation of this gene. Cyclin A expression is also induced in cells infected with this mutant virus. Since HMGA2 is important for cell proliferation and differentiation, particularly during embryogenesis, it is possible that the repression of HMGA2 expression during fetal development could contribute to the specific birth defects in HCMV-infected neonates.

* Corresponding author. Mailing address: Cellular and Molecular Medicine East, Room 2059, Mail Code 0712, 9500 Gilman Drive, University of California, San Diego, La Jolla, CA 92093-0712. Phone: (858) 822-4003. Fax: (858) 534-6083. E-mail: dspector{at}ucsd.edu.

Journal of Virology, October 2006, p. 9951-9961, Vol. 80, No. 20
0022-538X/06/$08.00+0     doi:10.1128/JVI.01300-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kapasi, A. J., Clark, C. L., Tran, K., Spector, D. H. (2009). Recruitment of cdk9 to the Immediate-Early Viral Transcriptosomes during Human Cytomegalovirus Infection Requires Efficient Binding to Cyclin T1, a Threshold Level of IE2 86, and Active Transcription. J. Virol. 83: 5904-5917 [Abstract] [Full Text]  
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  • Sanders, R. L., Clark, C. L., Morello, C. S., Spector, D. H. (2008). Development of Cell Lines That Provide Tightly Controlled Temporal Translation of the Human Cytomegalovirus IE2 Proteins for Complementation and Functional Analyses of Growth-Impaired and Nonviable IE2 Mutant Viruses. J. Virol. 82: 7059-7077 [Abstract] [Full Text]  


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