Nrf1 is paved as a new strategic avenue to prevent and treat cancer, neurodegenerative and other diseases

Yuan, Jianxin; Zhang, Shuwei; Zhang, Yiguo

doi:10.1016/j.taap.2018.09.037

Cited by 52 publications

(36 citation statements)

References 104 publications

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“…The membrane-topology of Nfe2l1 determines its selective proteolytic processing by proteasomes and/or other cytosolic proteases in close proximity to the ER, in order to yield distinct lengths of its isoforms, before its mature CNC-bZIP factor is translocated into the nucleus (44,61,62). Such the membrane-bound Nfe2l1 factor can also be activated in the unfolded protein response to the ER stress stimulated by tunicamycin (to inhibit its N-linked glycosylation) (38), in addition to its proteasomal 'bounce-back' response (63,64).…”

Section: Synergism Of Mouse Nfe2l1 Nrf1 Nfe2l2mentioning

confidence: 99%

Synergism and antagonism of two distinct, but confused, Nrf1 factors in integral regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription networks

Zhang

Deng

Xiang

et al. 2020

Preprint

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There is hitherto no literature available for explaining two distinct, but confused Nrf1 transcription factors, because they shared the same abbreviations from nuclear factor erythroid 2-related factor 1 (also called Nfe2l1) and nuclear respiratory factor (originally designated -Pal). Thus, we have here identified that Nfe2l1 Nrf1 and -Pal NRF1 exert synergistic and antagonistic roles in integrative regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription profiles. In mouse embryonic fibroblasts (MEFs), knockout of Nfe2l1 / leads to substantial decreases in expression levels of -Pal NRF1 and Nfe2l2, together with TFAM (mitochondrial transcription factor A) and other target genes. Similar inhibitory results were determined in Nfe2l2 / MEFs, with an exception that GSTa1 and Aldh1a1 were distinguishably up-regulated in Nfe2l1 / MEFs. Such synergistic contributions of Nfe2l1 and Nfe2l2 to the positive regulation of -Pal NRF1 and TFAM were validated in Keap1 / MEFs. However, human -Pal NRF1 expression was unaltered by hNfe2l1 / , hNfe2l2 /TA or even hNfe2l1 / +siNrf2, albeit TFAM was activated by Nfe2l1 but inhibited by Nfe2l2; such an antagonism occured in HepG2 cells. Conversely, almost all of mouse Nfe2l1, Nfe2l2 and co-target genes were down-expressed in -Pal NRF1/ MEFs. On the contrary, up-regulation of human Nfe2l1, Nfe2l2 and relevant reporter genes took place after silencing of -Pal NRF1 , but their down-regulation occurred upon ectopic expression of -Pal NRF1 .Furtherly, Pitx2 (pituitary homeobox 2) was also identified as a direct upstream regulator of Nfe2l1 and TFAM, besides -Pal NRF1 . Overall, these across-talks amongst Nfe2l1, Nfe2l2 and -Pal NRF1 , along with Pitx2, are integrated from the endoplasmic reticulum to the nuclear-to-mitochondrial communication for targeting TFAM, in order to finely tune the cellular respiratory and antioxidant gene transcription networks, albeit they differ between the mouse and the human. Keywords: Nfe2l1/Nrf1, Nfe2l2/Nrf2, -Pal NRF1 , TFAM, Pitx2, cap'n'collar (CNC), antioxidant response element (ARE), nuclear-to-mitochondrial respiratory system, and ER-nuclear-mitochondrial (ENUM) communication Running title: Two distinct Nrf1 factors responsible for cellular antioxidant and respiration.

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Section: Synergism Of Mouse Nfe2l1 Nrf1 Nfe2l2mentioning

confidence: 99%

Synergism and antagonism of two distinct, but confused, Nrf1 factors in integral regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription networks

Zhang

Deng

Xiang

et al. 2020

Preprint

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“…Collectively, together with transcriptomic sequencing, a model was herein proposed (as illustrated in Figure 6G), to provide a better explanation of the underlying mechanism(s) by which either activation or inactivation of the -catenin signaling towards target genes is dependent respectively on the absence or presence of Nrf1. Of note, most of all 26S proteasomal subunits are transcriptionally regulated by Nrf1, particularly in the proteasomal 'bounce-back' response to its limited inhibitor [14,25,53]. When such function of Nrf1 was stably silenced, all three active subunits 1, 2 and 5 (encoded by PSMB6, PSMB7 and PSMB5) of the 20S core proteasomal particle were down-regulated in the shNrf1expressing cells, which was roughly similar to those obtained from Nrf1 −/− (HEA157) cells ( Figure S2A, Table S1).…”

Section: Knockdown Of Nrf1 Causes -Catenin Activation and Translocatmentioning

confidence: 99%

“…Such opposing roles of Nrf2 in tumor prevention and progression have thereby led us to take account severely of its bidirectional potentials to implicate in cancer treatment. By contrast, Nrf1 is endowed with the unique remarkable features that are distinctive from Nrf2 [6,25]. This is based on the facts that gene-targeting strategies for knockout of Nrf1 are employed to create distinct animal models with significant pathological phenotypes [26][27][28][29][30][31].…”

mentioning

confidence: 99%

Nrf1 is endowed with a dominant tumor-repressing effect onto the Wnt/β-Catenin-dependent and -independent signaling networks in the human liver cancer

Chen

Wang

et al. 2019

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Our previous work revealed that Nrf1 exerts a tumor-repressing effect because its genomic loss (to yield Nrf1 −/− ) results in oncogenic activation of Nrf2 and target genes. Interestingly, -catenin is concurrently activated by loss of Nrf1 in a way similar to -catenin-driven liver tumor. However, a presumable relationship between Nrf1 and -catenin is not as yet established. Here, we demonstrate that Nrf1 enhanced ubiquitination of -catenin for targeting to proteasomal degradation. Conversely, knockdown of Nrf1 by its short-hairpin RNA (shNrf1) caused accumulation of -catenin so as to translocate the nucleus, allowing activation of a subset of Wnt−-catenin signaling responsive genes, which leads to the epithelial-mesenchymal transition (EMT) and related cellular processes. Such silencing of Nrf1 resulted in malgrowth of human hepatocellular carcinoma, along with malignant invasion and metastasis to the lung and liver in xenograft model mice. Further transcriptomic sequencing unraveled significant differences in the expression of both Wnt/-catenin-dependent and -independent responsive genes implicated in the cell process, shape and behavior of the shNrf1-expressing tumor. Notably, we identified that -catenin is not a target gene of Nrf1, but this CNC-bZIP factor contributes to differential or opposing expression of other critical genes, such as CDH1, Wnt5A, Wnt11A, FZD10, LEF, TCF4, SMAD4, MMP9, PTEN, PI3K, JUN and p53, each of which depends on the positioning of distinct cis-regulatory sequences (e.g., ARE and/or AP-1 binding sites) in the gene promoter contexts. In addition, altered expression profiles of some Wnt−-catenin signaling proteins were context-dependent, as accompanied by decreased abundances of Nrf1 in the clinic human hepatomas with distinct differentiation. Together, these results corroborate the rationale that Nrf1 acts as a bona fide dominant tumor-repressor, by its intrinsic inhibition of Wnt−-catenin signaling and relevant independent networks in cancer development and malignant progression.repressors Bach1 (BTB and CNC homology 1) and Bach2 [6,7], together with the recently-identified Nach (Nrf and CNC homology) proteins existing in marine bacteria to early diverging metazoans [3,4]. These CNC/Nach-bZIP family members share a common evolutionary ancestor with the Maf (musculoaponeurotic fibrosarcoma oncogene) family, including sMaf (small Maf) proteins [4]. They play a host of vital, and even indispensable, roles in regulating distinct subsets of target genes involved in antioxidant, detoxification, redox metabolism, proteasomal degradation, adaptive cytoprotection, and other physio-pathological responses to diverse cellular stresses [6][7][8]. Such genes are regulated transcriptionally by a functional heterodimer of each CNC-bZIP factor (except Skn-1) with a cognate partner sMaf or another bZIP protein, which directly binds the antioxidant and electrophile response elements (AREs/EpREs) and/or other cis-regulatory homologues (e.g., AP-1 binding site) within the gene promoter reg...

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“…Such concurrence of severe oxidative stress with UPR in mouse Nrf1 / livers results from down-regulation of antioxidant, detoxification and proteasomal genes. In the proteasomal compensatory response to limited extents of proteasome inhibitors [28], Nrf1 is subjected to the multistep processing of Nrf1 and its nuclear translocation [29], albeit the inhibition of proteasome-mediated ERAD is also one of the causes of ER stress [24,26,30]. These facts demonstrate that Nrf1 possesses an essential cytoprotective role against development of hepatosteatosis by maintaining the ER homeostasis, but the underlying mechanism remains unknown.…”

Section: Figure 1 Inhibition Of Nrf1 N-glycosylation By Tu In the Ermentioning

confidence: 99%

A unity of opposites in between Nrf1- and Nrf2-mediated responses to the endoplasmic reticulum stressor tunicamycin

Zhu¹,

Hu²,

Ru³

et al. 2019

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The water-soluble Nrf2 is accepted as a master regulator of antioxidant responses to cellular stress, it was also identified as a direct target of the endoplasmic reticulum (ER)-anchored PERK. However, the membrane-bound Nrf1 response to ER stress remains elusive. Herein, we report a unity of opposites in both Nrf1-and Nrf2-coordinated responses to the ER stressor tunicamycin (TU). The TU-inducible transcription of Nrf1 and Nrf2, as well as GCLM and HO-1, was accompanied by activation of ER stress signaling networks. The unfolded protein response (UPR) mediated by ATF6, IRE1 and PERK was significantly suppressed by Nrf1-specific knockout, but hyper-expression of Nrf2, GCLM and HO-1 was retained in Nrf1 / cells. By contrast, Nrf2 /TA cells with a genomic deletion of its transactivation domain resulted in significant decreases of GCLM, HO-1 and Nrf1; this was accompanied by partial decreases of IRE1 and ATF6, but not PERK, along with an obvious increase of ATF4. Notably, Nrf1 glycosylation and its trans-activity to mediate transcriptional expression of 26S proteasomal subunits were repressed by TU. This inhibitory effect was enhanced by Nrf1 / and Nrf2 /TA , but not by a constitutive activator caNrf2 N (that increased abundances of non-glycosylated and processed Nrf1). Furthermore, caNrf2 N also enhanced induction of PERK and IRE1 by TU, but reduced expression of ATF4 and HO-1. Such distinct roles of Nrf1 and Nrf2 are unified to maintain cell homeostasis by a series of coordinated ER-to-nuclear signaling responses to TU. Overall, Nrf1 acts in a cell-autonomous manner to determine transcription of most of UPR-target genes, albeit Nrf2 is also partially involved in this process.

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Nrf1 is paved as a new strategic avenue to prevent and treat cancer, neurodegenerative and other diseases

Cited by 52 publications

References 104 publications

Synergism and antagonism of two distinct, but confused, Nrf1 factors in integral regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription networks

Synergism and antagonism of two distinct, but confused, Nrf1 factors in integral regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription networks

Nrf1 is endowed with a dominant tumor-repressing effect onto the Wnt/β-Catenin-dependent and -independent signaling networks in the human liver cancer

A unity of opposites in between Nrf1- and Nrf2-mediated responses to the endoplasmic reticulum stressor tunicamycin

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