Apoptosis

, Volume 11, Issue 1, pp 5–13

Role of the unfolded protein response in cell death

Article

DOI: 10.1007/s10495-005-3088-0

Cite this article as:
Kim, R., Emi, M., Tanabe, K. et al. Apoptosis (2006) 11: 5. doi:10.1007/s10495-005-3088-0

Abstract

Unfolded protein response (UPR) is an important genomic response to endoplasmic reticulum (ER) stress. The ER chaperones, GRP78 and Gadd153, play critical roles in cell survival or cell death as part of the UPR, which is regulated by three signaling pathways: PERK/ATF4, IRE1/XBP1 and ATF6. During the UPR, accumulated unfolded protein is either correctly refolded, or unsuccessfully refolded and degraded by the ubiquitin-proteasome pathway. When the unfolded protein exceeds a threshold, damaged cells are committed to cell death, which is mediated by ATF4 and ATF6, as well as activation of the JNK/AP-1/Gadd153-signaling pathway. Gadd153 suppresses activation of Bcl-2 and NF-κB. UPR-mediated cell survival or cell death is regulated by the balance of GRP78 and Gadd153 expression, which is coregulated by NF-κB in accordance with the magnitude of ER stress. Less susceptibility to cell death upon activation of the UPR may contribute to tumor progression and drug resistance of solid tumors.

Keywords

cancer therapy cell death endoplasmic reticulum unfolded protein response 

Abbreviations

UPR

unfolded protein response

ER

endoplasmic reticulum

GRP

glucose-regulated protein

BiP

immunoglobulin binding protein

Gadd153

growth arrest and DNA damage-inducible protein 153

PERK

double-stranded RNA-activated protein kinase-like ER kinase

ATF

activating transcription factor

IRE-1

high inositol-requiring 1

XBP1

X-box binding protein 1

JNK

c-Jun N-terminal kinase

ASK1

apoptosis signal-regulating kinase

CHOP/Gadd153

CCAAT/enhancer-binding protein (C/EBP)-homologous protein/growth arrest and DNA damage-inducible protein 153

eIF

eukaryotic initiation factor

ERAD

ER-associated degradation

EDEM

ER degradation-enhancing α-mannosidase-like protein

TRF2

TNF receptor-associated factor 2

bZIP

basic leucine zipper

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  1. 1.International Radiation Information Center, Research Institute for Radiation Biology and MedicineHiroshima UniversityHiroshimaJapan
  2. 2.Departent of Surgical Oncology, Research Institute for Radiation Biology and MedicineHiroshima UniversityHiroshimaJapan
  3. 3.International Radiation Information Center, Research Institute for Radiation Biology and MedicineHiroshima UniversityHiroshimaJapan

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