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.
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 86DeltaSX-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 86DeltaSX-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.
Shlapobersky
Mark
M
Cellular and Molecular Medicine East, Room 2059, 9500 Gilman Drive, University of California-San Diego, La Jolla, CA 92093-0712, USA.
Sanders
Rebecca
R
Clark
Charles
C
Spector
Deborah H
DH
D002478:Cells, Cultured; D019925:Cyclin A / Q000096:biosynthesis / Q000235:genetics*; D003587:Cytomegalovirus / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D025743:HMGA2 Protein / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology*; D012313:RNA / Q000032:analysis / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis; D011995:Recombination, Genetic; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology; D014779:Virus Replication
D019925:Cyclin A; D025743:HMGA2 Protein; C088645:IE1 protein, cytomegalovirus; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D014764:Viral Proteins; D012313:RNA