The α1 subunit of GABAA receptor is repressed by c-Myc and is pro-apoptotic

✍ Scribed by Uri A. Vaknin; Stephen R. Hann

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 296 KB
• Volume: 97
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.20708

✦ Synopsis

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 α1 subunit of γ aminobutyric acid receptor (GABA~A~R‐α1) as a novel target of c‐myc. GABA~A~R 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 GABA~A~R‐α1 expression is rapidly and directly repressed by c‐myc. GABA~A~R‐α1 expression is elevated in c‐myc null cells and upregulation of GABA~A~R‐α1 correlates with downregulation of c‐myc protein expression during neuronal cell differentiation. We also show that overexpression of GABA~A~R‐α1 causes apoptosis, which is blocked by the coexpression of Bcl‐2 or Bcl‐X~L~. Induction of apoptosis is specific for the α1 subunit, since neither the β1 or β2 subunits of GABA~A~R induced apoptosis. Derepression of GABA~A~R‐α1 expression upon downregulation of c‐myc represents a unique apoptotic mechanism and a distinct function for the α1 subunit, independent of its role as a component of the GABA~A~R in the plasma membrane. In addition, the regulation of GABA~A~R‐α1 expression by c‐myc provides a potential direct role for the Myc proteins in neurological processes and neurodegenerative disorders. J. Cell. Biochem. 97: 1094–1103, 2006. © 2005 Wiley‐Liss, Inc.