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

Rajani Ravi; Gauri C. Bedi; Laura W. Engstrom; Qinwen Zeng; Bijoyesh Mookerjee; Céline Gélinas; Ephraim J. Fuchs; Atul Bedi

doi:10.1038/35070096

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

Rajani Ravi, Gauri C. Bedi, Laura W. Engstrom, Qinwen Zeng, Bijoyesh Mookerjee, Céline Gélinas, Ephraim J. Fuchs, Atul Bedi

School of Medicine

Research output: Contribution to journal › Article › peer-review

296 Scopus citations

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-κB induces expression of TRAIL-R1 and TRAIL-R2; conversely, a transdominant mutant of the inhibitory protein IκBα or a transactivation-deficient mutant of c-Rel reduces expression of either death receptor. Whereas NF-κB promotes death receptor expression, cytokine-mediated activation of the RelA subunit of NF-κB also increases expression of the apoptosis inhibitor, Bcl-x_L, and protects cells from TRAIL. Inhibition of NF-κB by blocking activation of the IκB kinase complex reduces Bcl-x_L expression and sensitizes tumour cells to TRAIL-induced apoptosis. The ability to induce death receptors or Bcl-x_L may explain the dual roles of NF-κB as a mediator or inhibitor of cell death during immune and stress responses.

Original language	English (US)
Pages (from-to)	409-416
Number of pages	8
Journal	Nature cell biology
Volume	3
Issue number	4
DOIs	https://doi.org/10.1038/35070096
State	Published - 2001

ASJC Scopus subject areas

Cell Biology

Access to Document

10.1038/35070096

Cite this

@article{e867d66c0c974e6ea56ff0e00f9fe165,

title = "Regulation of death receptor expression and TRAIL/Apo2L-induced apoptosis by NF-κB",

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-κB induces expression of TRAIL-R1 and TRAIL-R2; conversely, a transdominant mutant of the inhibitory protein IκBα or a transactivation-deficient mutant of c-Rel reduces expression of either death receptor. Whereas NF-κB promotes death receptor expression, cytokine-mediated activation of the RelA subunit of NF-κB also increases expression of the apoptosis inhibitor, Bcl-xL, and protects cells from TRAIL. Inhibition of NF-κB by blocking activation of the IκB kinase complex reduces Bcl-xL 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-κB as a mediator or inhibitor of cell death during immune and stress responses.",

author = "Rajani Ravi and Bedi, {Gauri C.} and Engstrom, {Laura W.} and Qinwen Zeng and Bijoyesh Mookerjee and C{\'e}line G{\'e}linas and Fuchs, {Ephraim J.} and Atul Bedi",

note = "Funding Information: ACKNOWLEDGEMENTS We thank B. Vogelstein for the p53+/+ and p53–/– HCT116 cells; T. Jacks for the p53–/– MEFs; W. El-Deiry for the vector encoding KILLER/DR5; A. A. Beg for providing RelA–/– mouse fibroblasts; S. Gerondakis and C. Snapper for providing c-Rel–/– fibroblasts and c-Rel–/– mice; and K. Bhalla for the HL-60-Neo and HL-60-Bcl-xL cells. This work was funded in part by grants from the NIH (National Cancer Institute), the US Army Medical Research and Materiel Command, Department of Defense Breast Cancer Research Program, and the American Cancer Society (to A.B.). A.B. is a recipient of Physician Scientist award from the Passano Foundation and a Scholar award from the Valvano Foundation for Cancer Research. Correspondence and requests for materials should be addressed to A.B.",

year = "2001",

doi = "10.1038/35070096",

language = "English (US)",

volume = "3",

pages = "409--416",

journal = "Nature cell biology",

issn = "1465-7392",

publisher = "Nature Publishing Group",

number = "4",

}

TY - JOUR

T1 - Regulation of death receptor expression and TRAIL/Apo2L-induced apoptosis by NF-κB

AU - Ravi, Rajani

AU - Bedi, Gauri C.

AU - Engstrom, Laura W.

AU - Zeng, Qinwen

AU - Mookerjee, Bijoyesh

AU - Gélinas, Céline

AU - Fuchs, Ephraim J.

AU - Bedi, Atul

N1 - Funding Information: ACKNOWLEDGEMENTS We thank B. Vogelstein for the p53+/+ and p53–/– HCT116 cells; T. Jacks for the p53–/– MEFs; W. El-Deiry for the vector encoding KILLER/DR5; A. A. Beg for providing RelA–/– mouse fibroblasts; S. Gerondakis and C. Snapper for providing c-Rel–/– fibroblasts and c-Rel–/– mice; and K. Bhalla for the HL-60-Neo and HL-60-Bcl-xL cells. This work was funded in part by grants from the NIH (National Cancer Institute), the US Army Medical Research and Materiel Command, Department of Defense Breast Cancer Research Program, and the American Cancer Society (to A.B.). A.B. is a recipient of Physician Scientist award from the Passano Foundation and a Scholar award from the Valvano Foundation for Cancer Research. Correspondence and requests for materials should be addressed to A.B.

PY - 2001

Y1 - 2001

N2 - 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-κB induces expression of TRAIL-R1 and TRAIL-R2; conversely, a transdominant mutant of the inhibitory protein IκBα or a transactivation-deficient mutant of c-Rel reduces expression of either death receptor. Whereas NF-κB promotes death receptor expression, cytokine-mediated activation of the RelA subunit of NF-κB also increases expression of the apoptosis inhibitor, Bcl-xL, and protects cells from TRAIL. Inhibition of NF-κB by blocking activation of the IκB kinase complex reduces Bcl-xL 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-κB as a mediator or inhibitor of cell death during immune and stress responses.

AB - 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-κB induces expression of TRAIL-R1 and TRAIL-R2; conversely, a transdominant mutant of the inhibitory protein IκBα or a transactivation-deficient mutant of c-Rel reduces expression of either death receptor. Whereas NF-κB promotes death receptor expression, cytokine-mediated activation of the RelA subunit of NF-κB also increases expression of the apoptosis inhibitor, Bcl-xL, and protects cells from TRAIL. Inhibition of NF-κB by blocking activation of the IκB kinase complex reduces Bcl-xL 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-κB as a mediator or inhibitor of cell death during immune and stress responses.

UR - http://www.scopus.com/inward/record.url?scp=0035067368&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035067368&partnerID=8YFLogxK

U2 - 10.1038/35070096

DO - 10.1038/35070096

M3 - Article

C2 - 11283615

AN - SCOPUS:0035067368

SN - 1465-7392

VL - 3

SP - 409

EP - 416

JO - Nature cell biology

JF - Nature cell biology

IS - 4

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this