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

Par-4(1) (prostate apoptosis response 4) is known to function at an early s tage in apoptosis in several different cell types, including neurons. On th e other hand, activation of the transcription factor NF-kappa B can prevent apoptosis in various cancer cells and neurons. We now report that overexpr ession of full-length Par-4 in cultured PC12 cells results in a suppression of basal NF-kappa B DNA-binding activity and NF-kappa B activation followi ng trophic factor withdrawal (TFW). The decreased NF-kappa B activity is co rrelated with enhanced apoptosis. Conversely, NF-kappa B activity is increa sed and vulnerability to apoptosis reduced in cells overexpressing a domina nt-negative form of Par-4. Par-4 overexpression or functional blockade had no effect on AP-1 DNA-binding activity. Expression of the antiapoptotic pro tein Bcl-2 was dramatically reduced in PC12 cells overexpressing Par-4. Our data suggest that suppression of NF-kappa B activation plays a major role in the proapoptotic function of Par-4. (C) 2000 Wiley-Liss, Inc.