Related Experiment Videos
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.
Abstract:
TRAIL (tumour-necrosis factor-related apoptosis ligand or Apo2L) triggers apoptosis through engagement of the death receptors TRAIL-R1 (also known as DR4) and TRAIL-R2 (DR5). Here we show that the c-Rel subunit of the transcription factor NF-kappaB induces expression of TRAIL-R1 and TRAIL-R2; conversely, a transdominant mutant of the inhibitory protein IkappaBalpha or a transactivation-deficient mutant of c-Rel reduces expression of either death receptor. Whereas NF-kappaB promotes death receptor expression, cytokine-mediated activation of the RelA subunit of NF-kappaB also increases expression of the apoptosis inhibitor, Bcl-xL, and protects cells from TRAIL. Inhibition of NF-kappaB by blocking activation of the IkappaB kinase complex reduces Bcl-x L expression and sensitizes tumour cells to TRAIL-induced apoptosis. The ability to induce death receptors or Bcl-xL may explain the dual roles of NF-kappaB as a mediator or inhibitor of cell death during immune and stress responses.
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.