Daunomycin is a potent inducer of p53 and NF-kappaB transcription factors. It is also able to increase the amount of the p21 cyclin-dependent kinase inhibitor. The human p21 promoter harbors p53-responsive elements and an NF-kappaB binding site. We demonstrated, in human breast and colon carcinoma cells, the binding of NF-kappaB dimers to the kappaB site and the transcriptional activation of the human p21 promoter by daunomycin and by NF-kappaB subunits, thereby confirming the functionality of this kappaB binding site. However, using different tumor cell lines where p53 or NF-kappaB was inactive, we showed that p21 activation and cell cycle arrest induced by daunomycin was p53-dependent and NF-kappaB-independent, whereas daunomycin-induced apoptosis was p53- and NF-kappaB-independent.