Effect of the Human Cytomegalovirus IE86 Protein on Expression of E2F-Responsive Genes: A DNA Microarray Analysis

We have previously reported that the immediate early (IE)-86 protein of human cytomegalovirus (HCMV) pushes the cell cycle toward S phase but inhibits cell division [Murphy, E. A., Streblow, D. N., Nelson, J. A. & Stinski, M. F. (2000) J. Virol. 74, 7108-7118]. We determined the cellular genes activated by the IE86 protein in permissive human fibroblast cells. A 4-fold or greater increase in the steady-state RNA from many cellular genes that regulate the cell cycle, the enzymes for DNA precursor synthesis, and the initiation of cellular DNA replication was detected by high-density DNA microarray analysis. Northern blot analysis confirmed the DNA microarray data. The viral IE86 protein induced a significant increase in the cellular steady-state RNA level from the B-myb, cyclin E, cdk-2, E2F-1, ribonucleotide reductase 1, ribonucleotide reductase 2, thymidylate synthetase, MCM3, and MCM7 genes, but actin RNA was not affected. Cellular genes regulated by the E2F transcription factors were strongly activated by the IE86 protein. In most cases, the cellular genes induced by the IE86 protein were also induced by HCMV infection. This study demonstrates the global array of cellular genes activated by the IE86 protein that pushes progression of the cell cycle from G0/G1toward the G1/S transition point.