Introduction: The Unfolded Protein Response

Research output: Chapter in Book/Report/Conference proceedingChapter


The translation and appropriate folding of proteins is critical for the maintenance of cellular function. This process is tightly controlled, and it can create a significant energy demand, particularly in secretory cells. Inadequate folding of proteins, as may occur with an insufficient energy supply, can cause unfolded, misfolded, or damaged proteins to accumulate in the endoplasmic reticulum. The consequent endoplasmic reticulum stress leads to activation of the unfolded protein response (UPR). In stressed mitochondria, a similar process is activated (mitochondrial unfolded protein response). The unfolded protein response is an ancient stress response that coordinates multiple functions in an attempt to restore metabolic homeostasis. In higher organisms, three signaling arms, driven respectively by PERK, ATF6, and IRE1α, may be activated. Together, the signaling from these arms coordinates specific cellular functions including autophagy, cell metabolism, and apoptosis. From a cell fate perspective, the outcome of activating the unfolded protein response can be either the restoration of homeostasis and normal cell function, or the failure to do so leading to aberrant cellular function (including neoplastic transformation) and/or the eventual initiation of an irreversible programmed cell death. Hence, activation of the unfolded proteins response can be either prosurvival or prodeath. This book covers many aspects of the unfolded protein response, from its roles in normal cell development and some aspects of immunity, through to those associated with neoplastic transformation and drug resistance in cancer. Also included is a chapter on the role of UPR-activated autophagy in specific neurodegenerative disorders. The primary focus of these chapters is the unfolded protein response as activated by an endoplasmic reticulum stress. While each chapter may be read independently, the reader will gain a much broader perspective of the critical roles of the unfolded protein response when the chapters are read collectively.

Original languageEnglish (US)
Title of host publicationCancer Drug Discovery and Development
PublisherHumana Press Inc.
Number of pages15
StatePublished - 2019
Externally publishedYes

Publication series

NameCancer Drug Discovery and Development
ISSN (Print)2196-9906
ISSN (Electronic)2196-9914

Bibliographical note

Publisher Copyright:
© 2019, Springer Nature Switzerland AG.


  • ATF4
  • ATF6
  • Autophagy
  • Cancer
  • Canonical signaling
  • Diabetes
  • Endoplasmic reticulum stress
  • GRP78
  • Hematopoietic
  • IRE1α
  • Metabolism
  • Neurodegenerative
  • PERK
  • Protein synthesis
  • Ribosome
  • Transcription
  • Translation
  • eIF2α


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