Roles of Nrf2 in cell proliferation and differentiation

Abstract

The Keap1-Nrf2 system plays pivotal roles in defense mechanisms by regulating cellular redox homeostasis. Nrf2 is an inducible transcription factor that activates a battery of genes encoding antioxidant proteins and phase II enzymes in response to oxidative stress and electrophilic xenobiotics. The activity of Nrf2 is regulated by Keap1, which promotes the ubiquitination and subsequent degradation of Nrf2 under normal conditions and releases the inhibited Nrf2 activity upon exposure to the stresses. Though an impressive contribution of the Keap1-Nrf2 system to the protection from exogenous and endogenous electrophilic insults has been well established, a line of evidence has suggested that the Keap1-Nrf2 system has various novel functions, particularly in cell proliferation and differentiation. Because the proliferation and differentiation of diverse cell types are often influenced and modulated by the cellular redox balance, Nrf2 has been considered to control these cellular processes by regulating the cellular levels of reactive oxygen species (ROS). In addition, analyses of the genome-wide distribution of Nrf2 have identified new sets of Nrf2 target genes whose products are involved in cell proliferation and differentiation but not necessarily in the regulation of oxidative stress. Considering the most characteristic features of Nrf2 as an inducible transcription factor, a newly emerged concept proposes that the Keap1-Nrf2 system translates environmental stresses into regulatory network signals in cell fate determination. In this review, we introduce the contribution of Nrf2 to lineage-specific differentiation, maintenance and differentiation of stem cells, and proliferation of normal and cancer cells, and we discuss how the response to fluctuating environments modulates cell behavior through the Keap1-Nrf2 system.

Cysteine Sulfenylation Directs IRE-1 to Activate the SKN-1/Nrf2 Antioxidant Response

“…Perhaps Keap1 arose in higher organisms to broaden or speed responsiveness to diverse electrophilic compounds. Nrf2 is either pathogenic or protective in certain cancers, diabetes, and other diseases (Murakami and Motohashi, 2015; O’Connell and Hayes, 2015; Uruno et al, 2013). It will be important to elucidate the extent to which the normal and disease-related functions of Nrf2 involve its regulation by Ire1α, and ER-associated ROS.…”

NRF2 Activation Impairs Quiescence and Bone Marrow Reconstitution Capacity of Hematopoietic Stem Cells

“…The KEAP1-NRF2 system has been shown to regulate cell proliferation and differentiation through the modulation of ROS levels in certain types of cells (9). Although ROS are required for HSPC proliferation and are increased upon the initiation of HSPC proliferation (33,34), excessive accumulation of ROS causes the functional decline of HSCs (35)(36)(37)(38).…”

“…In addition to redox regulation, recent studies have revealed critical contributions of the regulatory networks governed by NRF2 to a wider range of biological processes (9). In particular, the NRF2-mediated regulation of cell proliferation and differentiation has gained attention as a possible mechanism by which environmental stress can influence cell fate determination.…”

ROS-mediated Different Homeostasis of Murine Corneal Epithelial Progenitor Cell Line under Oxidative Stress

“…Activation of the NRF2 signaling pathway and its downstream factors, such as GSTP and NQO1, plays a vital role in the antioxidant activities3637. A recent study suggests that the activation of the endogenous NRF2 signaling pathway and the subsequent increases of antioxidant responsive element (ARE) members is an efficient and new approach for the exploration of next generation of antioxidants, which are different from the traditional and classic small molecule antioxidants which have potential side effects in clinical application34.…”