Astrocyte Apoptosis Induced by HIV-1 Transactivation of the c-kit Protooncogene

• Published in: Proceedings of the National Academy of Sciences - PNAS 1997-04, Vol.94 (8), p.3954-3959
• Main Authors: He, Jianglin, DeCastro, Carlos M., Vandenbark, George R., Busciglio, Jorge, Gabuzda, Dana
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Apoptosis; Astrocytes; Astrocytes - pathology; Astrocytes - virology; Biological Sciences; Brain; Cell lines; Cells, Cultured; Central nervous system; DNA; HIV; HIV 1; HIV Infections - metabolism; HIV Infections - pathology; HIV Infections - virology; Human immunodeficiency virus; human immunodeficiency virus 1; Humans; Infections; Medical research; Nervous system; Neurons; Plasmids; Proteins; Proto-Oncogene Proteins c-kit - metabolism; Transactivation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.8.3954

HIV-1 infection of the central nervous system (CNS) frequently causes dementia and other neurological disorders. The mechanisms of CNS injury in HIV-1 infection are poorly understood. Apoptosis of neurons and astrocytes is induced by HIV-1 infection in vitro and in brain tissue from AIDS patients, but the apoptotic stimuli have not been identified. We report herein that HIV-1 infection of primary brain cultures induces the receptor tyrosine kinase protooncogene c-kit and that high levels of c-Kit expression are associated with astrocyte apoptosis. Overexpression of c-Kit in an astrocyte-derived cell line in the absence of HIV-1 induces rapid apoptotic death. The apoptotic mechanism requires the c-Kit tyrosine kinase domain. The mechanism of c-kit induction by HIV-1 involves transactivation of the c-kit promoter by the HIV-1 Nef protein. These studies demonstrate that c-Kit can induce astrocyte apoptosis and suggest that this mechanism may play a role in CNS injury caused by HIV-1 infection. We propose that c-Kit can serve dual functions as a growth factor receptor or apoptosis inducer.