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Modulation of Oncogenic Phenotype in Human Glioma Cells by Cytomegalovirus IE1–Mediated Mitogenicity

¹ Department of Surgery, Division of Neurosurgery, and ² Department of Medicine, Division of Hematology/Oncology, University of Alabama School of Medicine, Birmingham, Alabama; and ³ Department of Neurosciences, California Pacific Medical Center Research Institute, San Francisco, California

Requests for reprints: Charles S. Cobbs, California Pacific Medical Center Research Institute, Suite 220, 475 Brannan Street, San Francisco, CA 94107. Phone: 415-317-7606; Fax: 415-600-1725; E-mail: charles.cobbs{at}gmail.com.

Key Words: Immediate early gene • HCMV • recombinant expression • PI-3 kinase/AKT • DNA synthesis • cell cycle

Recent evidence indicates that human cytomegalovirus (HCMV) infection occurs in a high percentage of human malignant gliomas in vivo, as the HCMV immediate early-1 (IE1) protein is detected in >90% of these tumors. The HCMV IE1 protein is essential for viral infection and has potent trans-activating and oncomodulatory properties. To investigate a potential role of HCMV in glioma biology, we stably expressed the HCMV IE1 gene product in immortalized and malignant human glial cells. Here we show that stable IE1 expression can differentially affect the growth of human glioblastoma cells, resulting in either growth proliferation or arrest. IE1 expression led to dysregulation of phosphatidylinositol 3-kinase/AKT activity, Rb phosphorylation, and expression of the p53 family of proteins. In U87 and U118 glioblastoma cells, IE1 induced cellular proliferation paralleled by reduction in steady-state expression level of Rb and p53 family proteins (including p53, p63, or p73) and simultaneous induction of the phosphatidylinositol 3-kinase/AKT signaling pathway. In contrast, IE1 expression in LN229 and U251 glioblastoma cells and immortalized human astrocytes was associated with increased expression of p53 family proteins, accompanied by growth arrest or lack of enhanced proliferation. Moreover, IE1 promoted cell cycle entry and DNA synthesis of human glioma cells on both stable expression in tumor-derived cell lines as well as transient expression in primary glioblastoma cells. These findings indicate that HCMV IE1 can significantly affect important oncogenic signaling pathways in glioblastoma cells. [Cancer Res 2008;68(3):724–30]

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