Astrocyte apoptosis induced by HIV-1 transactivation of the c-kit protooncogene.
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.
He
J
J
Dana-Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
deCastro
C M
CM
Vandenbark
G R
GR
Busciglio
J
J
Gabuzda
D
D
D017209:Apoptosis; D001253:Astrocytes / Q000473:pathology / Q000821:virology*; D002478:Cells, Cultured; D015658:HIV Infections / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D015497:HIV-1; D006801:Humans; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*
D019009:Proto-Oncogene Proteins c-kit