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

Oncogene. 2001 Feb 1;20(5):571-80. doi: 10.1038/sj.onc.1204124.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology*
  • Base Sequence
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics*
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism
  • Caspases / physiology*
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • Enzyme Activation
  • Gene Expression Regulation
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Molecular Sequence Data
  • NF-kappa B / genetics
  • NF-kappa B / physiology*
  • Transcriptional Activation / physiology
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / physiology*
  • Up-Regulation


  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases