p53 upregulates cFLIP, inhibits transcription of NF-kappa B-regulated genes and induces caspase-8-independent cell death in DLD-1 cells

One of the main functions of the tumor suppressor p53 is the induction of p rogrammed cell death, Here we investigated in detail the molecular mechanis ms that underlay p53 transactivation-dependent apoptosis in the human colon cancer cell line DLD-1, Although p53 upregulated the death receptors Fas, TRAIL-R1 and TRAIL-R2 in this cell line, p53-induced cell death occurred wi thout detectable caspase-8 activation whereas, activation of caspase-9 and caspase-3 was readily observed. In addition to the upregulation of death re ceptors, p53 induced the pro-apoptotic Bcl-2 family members Bik and Bak and downregulated the anti-apoptotic Bcl-xL protein. Moreover, in RNase protec tion assay analyses as well as in reporter gene analyses we found a p53-dep endent upregulation of the death receptor-inhibitory protein cFLIP. Togethe r, these data argue for a p53-mediated activation of the mitochondrial path way of apoptosis, In contrast to recently published data obtained in differ ent cellular systems, there was no evidence for an essential role of NF-kap paB in p53-induced cell death. Moreover, induction of p53 interfered,with T NF-induced NF-kappaB activation independently from apoptosis-induction.