ABSTRACT
The c-myc oncoprotein plays a critical role in the regulation of cellular proliferation and apoptosis. To mediate these biological functions, a variety of target genes are activated or repressed by c-myc, but few genes have yet been identified that directly mediate c-myc's role in proliferation or apoptosis. During a screen for genes that are repressed by c-myc, we identified the alpha1 subunit of gamma aminobutyric acid receptor (GABAAR-alpha1) as a novel target of c-myc. GABAAR is the major inhibitory neurotransmitter receptor in the mammalian central nervous system and is involved in developmental events in the brain, such as neurite outgrowth, neuronal survival, neuronal migration, and proliferation. We show here that GABAAR-alpha1 expression is rapidly and directly repressed by c-myc. GABAAR-alpha1 expression is elevated in c-myc null cells and upregulation of GABAAR-alpha1 correlates with downregulation of c-myc protein expression during neuronal cell differentiation. We also show that overexpression of GABAAR-alpha1 causes apoptosis, which is blocked by the coexpression of Bcl-2 or Bcl-XL. Induction of apoptosis is specific for the alpha1 subunit, since neither the beta1 or beta2 subunits of GABAAR induced apoptosis. Derepression of GABAAR-alpha1 expression upon downregulation of c-myc represents a unique apoptotic mechanism and a distinct function for the alpha1 subunit, independent of its role as a component of the GABAAR in the plasma membrane. In addition, the regulation of GABAAR-alpha1 expression by c-myc provides a potential direct role for the Myc proteins in neurological processes and neurodegenerative disorders.
