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Early growth response-1 is a regulator of DR5-induced apoptosis in colon cancer cells

D Mahalingam1, A Natoni, M Keane

  • 1Department of Biochemistry and National Centre of Biomedical Engineering Science, National University of Ireland, Galway, Ireland.

British Journal of Cancer
|January 21, 2010
PubMed
Abstract

Insights

Early growth response gene-1 (Egr-1) regulates sensitivity to TRAIL-induced apoptosis. Egr-1 inhibits DR5-mediated apoptosis, potentially by controlling c-FLIP(S) expression in colon cancer cells.

Area of Science:

  • Molecular biology
  • Cancer research
  • Cell signaling

Background:

  • Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis via death receptors DR4 and DR5.
  • Activation of DR4/DR5 can also promote inflammation and cell survival.
  • The regulation of these distinct cellular responses and the specific roles of DR4 versus DR5 remain unclear.

Purpose of the Study:

  • To investigate the role of early growth response gene-1 (Egr-1) in regulating TRAIL-induced apoptosis.
  • To differentiate the apoptotic pathways mediated by DR4 and DR5.
  • To elucidate the function of Egr-1 in TRAIL signaling.

Main Methods:

  • DNA microarray analysis to identify differentially expressed genes upon DR4/DR5 activation.
  • RT-PCR and western blotting to assess Egr-1 expression and TRAIL pathway proteins.
  • siRNA-mediated knockdown and dominant-negative Egr-1 overexpression to study Egr-1 function.

Main Results:

  • Egr-1 is constitutively expressed and induced by DR4/DR5 activation in colon cancer cells, regulating TRAIL sensitivity.
  • DR4 mediates type II (mitochondrion-dependent) apoptosis, while DR5 induces type I (mitochondrion-independent) apoptosis.
  • Egr-1 promotes c-FLIP expression; c-FLIP(S) specifically inhibits DR5 activation.

Conclusions:

  • Selective knockdown of c-FLIP(S) enhances DR5-induced apoptosis but not DR4-induced apoptosis.
  • Egr-1 acts as an inhibitor of the DR5-induced apoptotic pathway, likely through regulating c-FLIP(S) expression.

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