Notch-Nrf2 Axis: Regulation of <i>Nrf2</i> Gene Expression and Cytoprotection by Notch Signaling

Wakabayashi, Nobunao; Skoko, John; Chartoumpekis, Dionysios V.; Kimura, Shoko; Slocum, Stephen L.; Noda, Kentaro; Palliyaguru, Dushani L.; Fujimuro, Masahiro; Boley, Patricia A.; Tanaka, Yugo; Shigemura, Norihisa; Biswal, Shyam; Yamamoto, Masayuki; Kensler, Thomas W.

doi:10.1128/mcb.01408-13

Cited by 112 publications

(102 citation statements)

References 49 publications

(58 reference statements)

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“…These mice displayed resistance against acetaminophen, as adjudged by protection against elevated serum ALT levels. However, when the Nrf2 gene was disrupted from these mice, the protective effect against acetaminophen hepatotoxicity evoked by enhanced Notch signaling was eliminated [44]. This result indicated that the cytoprotective effect of Notch signaling might be mediated through Nrf2 signaling.…”

Section: Notch To Nrf2 Signalingmentioning

confidence: 64%

“…To this end, Nrf2 expression levels in liver specific NICD overexpressing mice (Rosa NICD/− ::AlbCre) were analyzed. It became evident that Notch to Nrf2 signaling was also functional in vivo [44]. All members of the Notch family can produce NICDs that act as transcriptional co-factors.…”

Section: Notch To Nrf2 Signalingmentioning

confidence: 99%

“…When the Nrf2 gene was deleted from liver specific NICD overexpressing mice, the excess microbranched phenotype and the total cast size of bile ducts returned to controls level. Thus, Notch to Nrf2 signaling probably contributes to total liver size and bile duct formation [44]. Sparks et al reported on ALT activity in a series of Notch-related genetic mutant mice (liver specific Notch2, both Notch1 and Notch2, Rbpjκ knock out mice).…”

Section: Notch To Nrf2 Signalingmentioning

confidence: 99%

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CROSSTALK BETWEEN Nrf2 AND NOTCH SIGNALING

Wakabayashi

2014

Free Radical Biology and Medicine

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The transcription factor, Nrf2 (nuclear factor, erythroid derived 2, like 2) belongs to the CNC-bZip protein family, forming a transcriptosome with its direct heterodimer partner, sMaf, and co-factors such as CBP/p300. Nrf2 binds to one or more ARE (Antioxidant Response Element) that are located in the gene regulatory regions of the hundreds of Nrf2 target genes. The ARE is a key enhancer that is activated in response to endogenous or exogenous stresses in order to maintain cellular and tissue homeostasis. Data emanating from gene expression microarray analyses comparing Nrf2-disrupted and wild-type mouse embryonic fibroblasts (MEF) showed that expression of Notch1 and Notch-signaling related genes were decreased in Nrf2-disrupted cells. This observation triggered our research on Nrf2-Notch crosstalk. A functional ARE has been identified upstream of the Notch1 major transcription start site. Furthermore, an Rbpjκ binding site is conserved on the promoters of Nrf2 among animal species. Notch1 is one of the transmembrane Notch family receptors, which drives Notch-signaling together with the Rbpjκ transcription factor. After canonically accepting ligands such as Jags and Deltas, the receptor undergoes cleavage to yield the Notch intracellular domain which translocates to the nucleus. Recent studies using conditional knockout mice indicate that Notch1 as well as Notch2 play important roles postnatally in liver development and in maintenance of hepatic function. In this review, we summarize current understanding of the role of reciprocal transcriptional regulation between Nrf2 and Notch in adult liver from studies using Nrf2, Keap1, and Notch1 genetically engineered mice.

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Section: Notch To Nrf2 Signalingmentioning

confidence: 64%

Section: Notch To Nrf2 Signalingmentioning

confidence: 99%

Section: Notch To Nrf2 Signalingmentioning

confidence: 99%

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CROSSTALK BETWEEN Nrf2 AND NOTCH SIGNALING

Wakabayashi

2014

Free Radical Biology and Medicine

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“…CCN6 acts like a brake on ETC activity and ATP synthesis, whereas Nrf2, which is a facilitator of mitochondrial metabolism (Holmstrom et al, 2013;Ludtmann et al, 2014;Piantadosi et al, 2008), possibly coordinates with CCN6 by repressing its expression. The transcriptional co-activator PGC1α, which is turned on by accumulated ROS from enhanced ETC activity in a muted-CCN6 background, might be able to promote expression of Nrf2 through its influence on Notch signaling (Sawada et al, 2014;Wakabayashi et al, 2014), and Nrf2 could repress CCN6 function furthermore.…”

Section: Discussionmentioning

confidence: 99%

CCN6 regulates mitochondrial function

Patra

Mahata

Padhan

et al. 2016

Journal of Cell Science

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Despite established links of CCN6, or Wnt induced signaling protein-3 (WISP3), with progressive pseudo rheumatoid dysplasia, functional characterization of CCN6 remains incomplete. In light of the documented negative correlation between accumulation of reactive oxygen species (ROS) and CCN6 expression, we investigated whether CCN6 regulates ROS accumulation through its influence on mitochondrial function. We found that CCN6 localizes to mitochondria, and depletion of CCN6 in the chondrocyte cell line C-28/I2 by using siRNA results in altered mitochondrial electron transport and respiration. Enhanced electron transport chain (ETC) activity of CCN6-depleted cells was reflected by increased mitochondrial ROS levels in association with augmented mitochondrial ATP synthesis, mitochondrial membrane potential and Ca 2+. Additionally, CCN6-depleted cells display ROS-dependent PGC1α (also known as PPARGC1A) induction, which correlates with increased mitochondrial mass and volume density, together with altered mitochondrial morphology. Interestingly, transcription factor Nrf2 (also known as NFE2L2) repressed CCN6 expression. Taken together, our results suggest that CCN6 acts as a molecular brake, which is appropriately balanced by Nrf2, in regulating mitochondrial function.

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“…Subsequently, Keap1 translocates into the nucleus and escorts nuclear export of Nrf2 for continuous proteasomal degradation in the cytoplasm, thus terminating Nrf2 activation. 3,4 Moreover, Keap1 can interact with other proteins and Nrf2 activity can be regulated by Keap1-independent mechanisms, [5][6][7] indicating their independent regulation and roles in different biological or pathological processes.…”

Section: Introductionmentioning

confidence: 99%