title: E2F1 localizes predominantly to neuronal cytoplasm and fails to induce expression of its transcriptional targets in human immunodeficiency virus-induced neuronal damage.
abstract: As human immunodeficiency virus (HIV) does not induce neuronal damage by direct infection, the mechanisms of neuronal damage or loss in HIV-associated dementia (HAD) remain unclear. We have shown previously that immunoreactivity of transcription factor, E2F1, increases in neurons, localizing predominantly to the cytoplasm, in HIV-associated pathologies. Here we confirm that E2F1 localization is predominantly cytoplasmic in primary postmitotic neurons in vitro and cortical neurons in vivo. To determine whether E2F1 contributes to neuronal death in HAD via transactivation of target promoters, we assessed the mRNA and protein levels of several classical E2F1 transcriptional targets implicated in cell cycle progression and apoptosis in an in vitro model of HIV-induced neurotoxicity and in cortical autopsy tissue from patients infected with HIV. By Q-PCR, we show that mRNA levels of E2F1 transcriptional targets implicated in cell cycle progression (E2F1, Cyclin A, proliferating cell nuclear antigen (PCNA), and dyhydrofolate reductase (DHFR)) and apoptosis (caspases 3, 8, 9 and p19(ARF)) remain unchanged in an in vitro model of HIV-induced neurotoxicity. Further, we show that protein levels of p19(ARF), Cyclin A, and PCNA are not altered in vitro or in the cortex of patients with HAD. We propose that the predominantly cytoplasmic localization of E2F1 in neurons may account for the lack of E2F1 target transactivation in neurons responding to HIV-induced neurotoxicity.
authors.affiliation: Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104-6030, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Nikhil
authors.initials: N
authors.lastname: Shyam
authors.forename: Jenhao H
authors.initials: JH
authors.lastname: Ting
authors.forename: Cagla
authors.initials: C
authors.lastname: Akay
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Lindl
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Jordan-Sciutto
mesh_terms: D015526:AIDS Dementia Complex / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D019925:Cyclin A / Q000096:biosynthesis / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D006678:HIV / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000821:virology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013762:Tetrahydrofolate Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis / Q000235:genetics
chemical_list: D019925:Cyclin A; D050687:E2F1 Transcription Factor; C493755:E2f1 protein, rat; D018809:Proliferating Cell Nuclear Antigen; D025803:Tumor Suppressor Protein p14ARF; C508715:p19(ARF) protein, rat; D013762:Tetrahydrofolate Dehydrogenase; D020169:Caspases