Role of the transcription factor E2F1 in CXCR4-mediated neurotoxicity and HIV neuropathology

• Published in: Neurobiology of disease Vol. 25; no. 1; pp. 17 - 26
• Main Authors: Shimizu, Saori, Khan, Muhammad Z., Hippensteel, Randi L, Parkar, Anjum, Raghupathi, Ramesh, Meucci, Olimpia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2007; Elsevier
• Subjects: Adult; Aged; AIDS Dementia Complex - pathology; Animals; Apoptosis - genetics; Blotting, Western; Brain - pathology; Cdc2; Cell cycle proteins; Cell Nucleus - metabolism; Cells, Cultured; Chemokines; E2F1 Transcription Factor - genetics; E2F1 Transcription Factor - physiology; Electrophoretic Mobility Shift Assay; Environment; Female; gp120; HIV Envelope Protein gp120 - genetics; HIV Infections - pathology; Human immunodeficiency virus; Humans; Immunoblotting; Immunohistochemistry; Luciferases - genetics; Male; Mice; Mice, Knockout; Microscopy, Fluorescence; Middle Aged; Neurology; Neuronal death; Neurons - physiology; Neurotoxicity Syndromes - pathology; Rats; Receptor Cross-Talk - physiology; Receptors, CXCR4 - physiology; Reverse Transcriptase Polymerase Chain Reaction; Survival Analysis; Transfection; Up-Regulation - genetics; Up-Regulation - physiology; SIVE; AIDS; CNS; HAD; Cdc2; Rb; HIVE; HIV; Neuronal death; gp120; Cell cycle proteins; Chemokines; HAART; acquired immunodeficiency syndrome; central nervous system; simian immunodeficiency virus encephalitis; HIV-associated dementia; retinoblastoma; highly active antiretroviral therapy; human immunodeficiency virus; HIV encephalopathy
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2006.08.004

This study sought to determine the role of the transcription factor E2F1 in CXCR4-mediated neurotoxicity and HIV neuropathology. We studied the effect of the HIV envelope protein gp120 on the expression of E2F1-dependent apoptotic proteins in human and rodent neurons and examined the expression pattern of E2F1 in the brain of HIV-infected individuals. Our findings suggest that in cultured neurons gp120 increased E2F1 levels in the nucleus, stimulated its transcriptional activity and enhanced the expression of the E2F1 target proteins Cdc2 and Puma. Studies with neuronal cultures from E2F1 deficient mice demonstrated that the transcription factor is required for gp120-induced neurotoxicity and up-regulation of Cdc2 and Puma. Levels of E2F1 protein were greater in the nucleus of neurons in brains of HIV-infected patients exhibiting dementia when compared to HIV-negative subjects or HIV-positive neurologically normal patients. Overall, these studies indicate that E2F1 is primarily involved in CXCR4-mediated neurotoxicity and HIV neuropathogenesis.