Pro-apoptotic action of Par-4 involves inhibition of NF-κB activity and suppression of Bcl-2 expression

Par-4¹ (prostate apoptosis response 4) is known to function at an early stage in apoptosis in several different cell types, including neurons. On the other hand, activation of the transcription factor NF-κB can prevent apoptosis in various cancer cells and neurons. We now report that overexpression of full-length Par-4 in cultured PC12 cells results in a suppression of basal NF-κB DNA-binding activity and NF-κB activation following trophic factor withdrawal (TFW). The decreased NF-κB activity is correlated with enhanced apoptosis. Conversely, NF-κB activity is increased and vulnerability to apoptosis reduced in cells overexpressing a dominant- negative form of Par-4. Par-4 overexpression or functional blockade had no effect on AP-1 DNA-binding activity. Expression of the antiapoptotic protein Bcl-2 was dramatically reduced in PC12 cells overexpressing Par-4. Our data suggest that suppression of NF-κB activation plays a major role in the proapoptotic function of Par-4. (C) 2000 Wiley-Liss, Inc.