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

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Regulation of death receptor expression and TRAIL/Apo2L-induced apoptosis by NF-kappaB

R Ravi1, G C Bedi, L W Engstrom

  • 1Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, Maryland 21231, USA.

Nature Cell Biology
|April 3, 2001
PubMed

Insights

The transcription factor NF-kappaB, specifically its c-Rel subunit, regulates expression of death receptors TRAIL-R1 and TRAIL-R2. NF-kappaB also influences apoptosis by controlling Bcl-xL, impacting cell sensitivity to TRAIL-induced cell death.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Immunology

Background:

  • Tumour-necrosis factor-related apoptosis ligand (TRAIL) induces apoptosis via death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5).
  • The transcription factor NF-kappaB plays a complex role in cellular responses, including apoptosis.
  • Understanding NF-kappaB's regulation of TRAIL signaling is crucial for cancer therapy and immune responses.

Purpose of the Study:

  • To investigate the role of the c-Rel subunit of NF-kappaB in regulating TRAIL death receptor expression.
  • To determine how NF-kappaB activation influences the expression of the apoptosis inhibitor Bcl-xL.
  • To elucidate the dual functions of NF-kappaB in mediating or inhibiting apoptosis.

Main Methods:

  • Utilizing transdominant mutants of IkappaBalpha and transactivation-deficient c-Rel mutants to assess NF-kappaB's effect on death receptor expression.
  • Employing cytokine-mediated activation to study the impact of RelA on Bcl-xL expression.
  • Inhibiting NF-kappaB activation via the IkappaB kinase complex to evaluate its effect on Bcl-xL and TRAIL sensitivity.

Main Results:

  • The c-Rel subunit of NF-kappaB was found to induce the expression of TRAIL-R1 and TRAIL-R2.
  • Conversely, inhibition of NF-kappaB signaling led to reduced expression of these death receptors.
  • Cytokine-mediated NF-kappaB activation (RelA) increased Bcl-xL expression, conferring resistance to TRAIL, while NF-kappaB inhibition sensitized cells to TRAIL.

Conclusions:

  • NF-kappaB, through its subunits c-Rel and RelA, directly regulates the expression of TRAIL death receptors and the apoptosis inhibitor Bcl-xL.
  • These regulatory functions explain the observed dual role of NF-kappaB as both a promoter and inhibitor of apoptosis.
  • Targeting NF-kappaB signaling could modulate TRAIL-induced apoptosis in cancer treatment and immune regulation.

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