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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Induction of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not growth arrest

G S Wu1, T F Burns, E R McDonald

  • 1Department of Medicine, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine Philadelphia 19104, USA.

Oncogene
|December 22, 1999
PubMed

Insights

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor, KILLER/DR5, is upregulated during p53-dependent apoptosis but not cell cycle arrest. This suggests a specific role for KILLER/DR5 in apoptosis following DNA damage.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The TRAIL death receptor, KILLER/DR5, is known to be induced by DNA-damaging agents in p53-expressing cells.
  • p53 is a critical tumor suppressor protein that regulates cell cycle arrest and apoptosis in response to DNA damage.

Purpose of the Study:

  • To investigate the differential regulation of KILLER/DR5 and p21WAF1/CIP1 expression by the p53 pathway.
  • To determine whether KILLER/DR5 induction is specific to apoptosis or also occurs during cell cycle arrest.

Main Methods:

  • Utilized inducible p53 expression systems in GM glioblastoma cells and normal lung fibroblasts (WI38).
  • Exposed cells to dexamethasone or ionizing irradiation to induce DNA damage and p53 activation.
  • Analyzed gene expression of KILLER/DR5 and p21WAF1/CIP1 using quantitative methods.
  • Investigated the role of the ATM-p53 pathway in KILLER/DR5 regulation using cells from Ataxia Telangiectasia patients.
  • Assessed the impact of transcriptional inhibition (Actinomycin D) on KILLER/DR5 and p21 induction.

Main Results:

  • GM glioblastoma cells with inducible p53 arrested the cell cycle and upregulated p21 but not KILLER/DR5 upon dexamethasone treatment.
  • WI38 fibroblasts undergoing irradiation-induced cell cycle arrest also upregulated p21 but not KILLER/DR5.
  • KILLER/DR5 upregulation was impaired in irradiated lymphoblastoid cells from Ataxia Telangiectasia patients, indicating a role for the ATM-p53 pathway.
  • Actinomycin D blocked both KILLER/DR5 and p21 induction in cells undergoing p53-dependent apoptosis.

Conclusions:

  • The p53-dependent transcriptional induction of the KILLER/DR5 death receptor is specifically linked to apoptosis.
  • KILLER/DR5 is not induced in cells undergoing exclusively p53-dependent G1 cell cycle arrest.
  • The findings highlight a distinct regulatory mechanism for KILLER/DR5 compared to other p53 target genes like p21.

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