Molecular mechanisms of Nrf2 regulation and how these influence chemical modulation for disease intervention

Bryan Harder, Tao Jiang, Tongde Wu, Shasha Tao, Montserrat Rojo De La Vega, Wang Tian, Eli Chapman, Donna Zhang

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Nrf2 (nuclear factor erytheroid-derived-2-like 2) transcriptional programmes are activated by a variety of cellular stress conditions to maintain cellular homoeostasis. Under non-stress conditions, Nrf2 is under tight regulation by the ubiquitin proteasome system (UPS). Detailed mechanistic investigations have shown the Kelch-like ECH-associated protein 1 (Keap1)-cullin3 (Cul3)-ring-box1 (Rbx1) E3-ligase to be the primary Nrf2 regulatory system. Recently, both beta-transducin repeat-containing E3 ubiquitin protein ligase (β-TrCP) and E3 ubiquitin-protein ligase synoviolin (Hrd1) have been identified as novel E3 ubiquitin ligases that negatively regulate Nrf2 through Keap1-independent mechanisms. In addition to UPS-mediated regulation of Nrf2, investigations have revealed a cross-talk between Nrf2 and the autophagic pathway resulting in activation of Nrf2 in a non-canonical manner. In addition to regulation at the protein level, Nrf2 was recently shown to be regulated at the transcriptional level by oncogenic K-rat sarcoma (Ras). A consequence of these differential regulatory mechanisms is the dual role of Nrf2 in cancer: the canonical, protective role and the non-canonical 'dark-side' of Nrf2. Based on the protective role of Nrf2, a vast effort has been dedicated towards identifying novel chemical inducers of Nrf2 for the purpose of chemoprevention. On the other hand, upon malignant transformation, some cancer cells have a constitutively high level of Nrf2 offering a growth advantage, as well as rendering cancer cells resistant to chemotherapeutics. This discovery has led to a new paradigm in cancer treatment; the initially counterintuitive use of Nrf2 inhibitors as adjuvants in chemotherapy. Herein, we will discuss the mechanisms of Nrf2 regulation and how this detailed molecular understanding can be leveraged to develop Nrf2 modulators to prevent diseases, mitigate disease progression or overcome chemoresistance.

Original languageEnglish (US)
Pages (from-to)680-686
Number of pages7
JournalBiochemical Society Transactions
Volume43
DOIs
StatePublished - Aug 1 2015

Fingerprint

Ubiquitin-Protein Ligases
Modulation
Proteasome Endopeptidase Complex
Ubiquitin
Cells
Transducin
Neoplasms
Proteins
Oncology
Chemotherapy
Modulators
Chemoprevention
Rats
Adjuvant Chemotherapy
Sarcoma
Chemical activation
Disease Progression
Homeostasis
Growth

Keywords

  • Chemoprevention/chemoresistance
  • Hrd1
  • Kelch-like ech-associated protein 1 (Keap1)
  • Nuclear factor erytheroid-derived-2-like 2 (Nrf2)
  • Reactive oxygen species (ROS)
  • Ubiquitin proteasome system (UPS)

ASJC Scopus subject areas

  • Biochemistry

Cite this

Molecular mechanisms of Nrf2 regulation and how these influence chemical modulation for disease intervention. / Harder, Bryan; Jiang, Tao; Wu, Tongde; Tao, Shasha; De La Vega, Montserrat Rojo; Tian, Wang; Chapman, Eli; Zhang, Donna.

In: Biochemical Society Transactions, Vol. 43, 01.08.2015, p. 680-686.

Research output: Contribution to journalArticle

Harder, Bryan ; Jiang, Tao ; Wu, Tongde ; Tao, Shasha ; De La Vega, Montserrat Rojo ; Tian, Wang ; Chapman, Eli ; Zhang, Donna. / Molecular mechanisms of Nrf2 regulation and how these influence chemical modulation for disease intervention. In: Biochemical Society Transactions. 2015 ; Vol. 43. pp. 680-686.
@article{a8448b74e4f744039fb40d860d19e8d9,
title = "Molecular mechanisms of Nrf2 regulation and how these influence chemical modulation for disease intervention",
abstract = "Nrf2 (nuclear factor erytheroid-derived-2-like 2) transcriptional programmes are activated by a variety of cellular stress conditions to maintain cellular homoeostasis. Under non-stress conditions, Nrf2 is under tight regulation by the ubiquitin proteasome system (UPS). Detailed mechanistic investigations have shown the Kelch-like ECH-associated protein 1 (Keap1)-cullin3 (Cul3)-ring-box1 (Rbx1) E3-ligase to be the primary Nrf2 regulatory system. Recently, both beta-transducin repeat-containing E3 ubiquitin protein ligase (β-TrCP) and E3 ubiquitin-protein ligase synoviolin (Hrd1) have been identified as novel E3 ubiquitin ligases that negatively regulate Nrf2 through Keap1-independent mechanisms. In addition to UPS-mediated regulation of Nrf2, investigations have revealed a cross-talk between Nrf2 and the autophagic pathway resulting in activation of Nrf2 in a non-canonical manner. In addition to regulation at the protein level, Nrf2 was recently shown to be regulated at the transcriptional level by oncogenic K-rat sarcoma (Ras). A consequence of these differential regulatory mechanisms is the dual role of Nrf2 in cancer: the canonical, protective role and the non-canonical 'dark-side' of Nrf2. Based on the protective role of Nrf2, a vast effort has been dedicated towards identifying novel chemical inducers of Nrf2 for the purpose of chemoprevention. On the other hand, upon malignant transformation, some cancer cells have a constitutively high level of Nrf2 offering a growth advantage, as well as rendering cancer cells resistant to chemotherapeutics. This discovery has led to a new paradigm in cancer treatment; the initially counterintuitive use of Nrf2 inhibitors as adjuvants in chemotherapy. Herein, we will discuss the mechanisms of Nrf2 regulation and how this detailed molecular understanding can be leveraged to develop Nrf2 modulators to prevent diseases, mitigate disease progression or overcome chemoresistance.",
keywords = "Chemoprevention/chemoresistance, Hrd1, Kelch-like ech-associated protein 1 (Keap1), Nuclear factor erytheroid-derived-2-like 2 (Nrf2), Reactive oxygen species (ROS), Ubiquitin proteasome system (UPS)",
author = "Bryan Harder and Tao Jiang and Tongde Wu and Shasha Tao and {De La Vega}, {Montserrat Rojo} and Wang Tian and Eli Chapman and Donna Zhang",
year = "2015",
month = "8",
day = "1",
doi = "10.1042/BST20150020",
language = "English (US)",
volume = "43",
pages = "680--686",
journal = "Biochemical Society Transactions",
issn = "0300-5127",
publisher = "Portland Press Ltd.",

}

TY - JOUR

T1 - Molecular mechanisms of Nrf2 regulation and how these influence chemical modulation for disease intervention

AU - Harder, Bryan

AU - Jiang, Tao

AU - Wu, Tongde

AU - Tao, Shasha

AU - De La Vega, Montserrat Rojo

AU - Tian, Wang

AU - Chapman, Eli

AU - Zhang, Donna

PY - 2015/8/1

Y1 - 2015/8/1

N2 - Nrf2 (nuclear factor erytheroid-derived-2-like 2) transcriptional programmes are activated by a variety of cellular stress conditions to maintain cellular homoeostasis. Under non-stress conditions, Nrf2 is under tight regulation by the ubiquitin proteasome system (UPS). Detailed mechanistic investigations have shown the Kelch-like ECH-associated protein 1 (Keap1)-cullin3 (Cul3)-ring-box1 (Rbx1) E3-ligase to be the primary Nrf2 regulatory system. Recently, both beta-transducin repeat-containing E3 ubiquitin protein ligase (β-TrCP) and E3 ubiquitin-protein ligase synoviolin (Hrd1) have been identified as novel E3 ubiquitin ligases that negatively regulate Nrf2 through Keap1-independent mechanisms. In addition to UPS-mediated regulation of Nrf2, investigations have revealed a cross-talk between Nrf2 and the autophagic pathway resulting in activation of Nrf2 in a non-canonical manner. In addition to regulation at the protein level, Nrf2 was recently shown to be regulated at the transcriptional level by oncogenic K-rat sarcoma (Ras). A consequence of these differential regulatory mechanisms is the dual role of Nrf2 in cancer: the canonical, protective role and the non-canonical 'dark-side' of Nrf2. Based on the protective role of Nrf2, a vast effort has been dedicated towards identifying novel chemical inducers of Nrf2 for the purpose of chemoprevention. On the other hand, upon malignant transformation, some cancer cells have a constitutively high level of Nrf2 offering a growth advantage, as well as rendering cancer cells resistant to chemotherapeutics. This discovery has led to a new paradigm in cancer treatment; the initially counterintuitive use of Nrf2 inhibitors as adjuvants in chemotherapy. Herein, we will discuss the mechanisms of Nrf2 regulation and how this detailed molecular understanding can be leveraged to develop Nrf2 modulators to prevent diseases, mitigate disease progression or overcome chemoresistance.

AB - Nrf2 (nuclear factor erytheroid-derived-2-like 2) transcriptional programmes are activated by a variety of cellular stress conditions to maintain cellular homoeostasis. Under non-stress conditions, Nrf2 is under tight regulation by the ubiquitin proteasome system (UPS). Detailed mechanistic investigations have shown the Kelch-like ECH-associated protein 1 (Keap1)-cullin3 (Cul3)-ring-box1 (Rbx1) E3-ligase to be the primary Nrf2 regulatory system. Recently, both beta-transducin repeat-containing E3 ubiquitin protein ligase (β-TrCP) and E3 ubiquitin-protein ligase synoviolin (Hrd1) have been identified as novel E3 ubiquitin ligases that negatively regulate Nrf2 through Keap1-independent mechanisms. In addition to UPS-mediated regulation of Nrf2, investigations have revealed a cross-talk between Nrf2 and the autophagic pathway resulting in activation of Nrf2 in a non-canonical manner. In addition to regulation at the protein level, Nrf2 was recently shown to be regulated at the transcriptional level by oncogenic K-rat sarcoma (Ras). A consequence of these differential regulatory mechanisms is the dual role of Nrf2 in cancer: the canonical, protective role and the non-canonical 'dark-side' of Nrf2. Based on the protective role of Nrf2, a vast effort has been dedicated towards identifying novel chemical inducers of Nrf2 for the purpose of chemoprevention. On the other hand, upon malignant transformation, some cancer cells have a constitutively high level of Nrf2 offering a growth advantage, as well as rendering cancer cells resistant to chemotherapeutics. This discovery has led to a new paradigm in cancer treatment; the initially counterintuitive use of Nrf2 inhibitors as adjuvants in chemotherapy. Herein, we will discuss the mechanisms of Nrf2 regulation and how this detailed molecular understanding can be leveraged to develop Nrf2 modulators to prevent diseases, mitigate disease progression or overcome chemoresistance.

KW - Chemoprevention/chemoresistance

KW - Hrd1

KW - Kelch-like ech-associated protein 1 (Keap1)

KW - Nuclear factor erytheroid-derived-2-like 2 (Nrf2)

KW - Reactive oxygen species (ROS)

KW - Ubiquitin proteasome system (UPS)

UR - http://www.scopus.com/inward/record.url?scp=84938694329&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84938694329&partnerID=8YFLogxK

U2 - 10.1042/BST20150020

DO - 10.1042/BST20150020

M3 - Article

C2 - 26551712

AN - SCOPUS:84938694329

VL - 43

SP - 680

EP - 686

JO - Biochemical Society Transactions

JF - Biochemical Society Transactions

SN - 0300-5127

ER -