Journal
ONCOGENE
Volume 20, Issue 5, Pages 571-580Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1204124
Keywords
apoptosis; FLIP; NF-kappa B; p53; caspase; death receptors
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One of the main functions of the tumor suppressor p53 is the induction of programmed cell death, Here we investigated in detail the molecular mechanisms 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 without detectable caspase-8 activation whereas, activation of caspase-9 and caspase-3 was readily observed. In addition to the upregulation of death receptors, p53 induced the pro-apoptotic Bcl-2 family members Bik and Bak and downregulated the anti-apoptotic Bcl-xL protein. Moreover, in RNase protection assay analyses as well as in reporter gene analyses we found a p53-dependent upregulation of the death receptor-inhibitory protein cFLIP. Together, these data argue for a p53-mediated activation of the mitochondrial pathway of apoptosis, In contrast to recently published data obtained in different cellular systems, there was no evidence for an essential role of NF-kappaB in p53-induced cell death. Moreover, induction of p53 interfered,with TNF-induced NF-kappaB activation independently from apoptosis-induction.
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