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Open Access Publications from the University of California

Scholarly Works (34 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (1996)

    Cover page: Isolation of the Nrf-1 gene, a novel ubiquitous bZIP transcription factor necessary for erythropoiesis
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2014)
      Cover page: Making light of stress
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      • Peer Reviewed
      UC Irvine Previously Published Works (2015)
      Herpud1 is an ER-localized protein that contributes to endoplasmic reticulum (ER) homeostasis by participating in the ER-associated protein degradation pathway. The Nrf1 transcription factor is important in cellular stress pathways. We show that loss of Nrf1 function results in decreased Herpud1 expression in cells and liver tissues. Expression of Herpud1 increases in response to ER stress, but not in Nrf1 knockout cells. Transactivation studies show that Nrf1 acts through antioxidant response elements located in the Herpud1 promoter, and chromatin immunoprecipitation demonstrates that Herpud1 is a direct Nrf1 target gene. These results indicate that Nrf1 is a transcriptional activator of Herpud1 expression during ER stress, and they suggest Nrf1 is a key player in the regulation of the ER stress response in cells.
        Cover page: Induction of Herpud1 expression by ER stress is regulated by Nrf1
        • Thesis
        • Peer Reviewed
        UC Irvine Electronic Theses and Dissertations (2016)

        The Nrf1 and Nrf2 (also known as NFE2L1 and NFE2L2) transcription factors are critical regulators of genes involved in defense against oxidative stress. Previous studies have suggested that Nrf2 plays a role in adipogenesis in vitro, and deletion of the Nrf2 gene protects against diet-induced obesity in mice. Here, we demonstrate that loss of either Nrf1 or Nrf2 results in a lean phenotype. Resistance to diet-induced obesity in Nrf2-/- mice is associated with a 20-30% increase in energy expenditure. This increase in whole animal energy expenditure is mirrored in the white adipose tissue of Nrf2-/- animals, which exhibit greater oxygen consumption in isolated tissue explants. Nrf2-/- WAT showed a greater than two-fold increase in Ucp1 gene expression along with increased expression of a variety of brown adipose tissue markers. Cell data mirrored that of animals with oxygen consumption increased nearly 2.5 fold in Nrf2 deficient fibroblasts. Oxidative stress induced by glucose oxidase resulted in increased Ucp1 expression and oxygen consumption. Conversely, antioxidant chemicals, such as N-acetylcysteine and MnTBAP, and SB203580, a known suppressor of Ucp1 expression, decreased Ucp1 and oxygen consumption in Nrf2 deficient fibroblasts. Examination of animals deficient in Nrf1 specifically in adipose tissue showed similar findings with increased expression of UCP1 and brown adipose tissue genes in the white adipose tissue. Additionally, Nrf1 deficient mice expressed higher levels of Metrnl1, a factor associated with increased Ucp1 levels. These findings suggest that modulating Nrf1 and Nrf2 levels in adipose tissue may be a novel means to regulate energy balance as a treatment of obesity and related clinical disorders.

          Cover page: Functional analysis of Nrf1 and Nrf2 transcription factors in adipose tissue
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2016)
          Nrf1 (also referred to as NFE2L1) is a member of the CNC-bZIP family of transcription factors that are characterized by a highly conserved CNC-domain, and a basic-leucine zipper domain required for dimerization and DNA binding. Nrf1 is ubiquitously expressed across tissue and cell types as various isoforms, and is induced by stress signals from a broad spectrum of stimuli. Evidence indicates that Nrf1 plays an important role in regulating a range of cellular functions including oxidative stress response, differentiation, inflammatory response, metabolism, and maintaining proteostasis. Thus, Nrf1 has been implicated in the pathogenesis of various disease processes including cancer development, and degenerative and metabolic disorders. This review summarizes our current understanding of Nrf1 and the molecular mechanism underlying its regulation and action in different cellular functions.
            Cover page: Nuclear Factor Erythroid-2 Like 1 (NFE2L1): Structure, function and regulation
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2022)
            Patulin is a mycotoxin produced by a variety of molds that is found in various food products. The adverse health effects associated with exposure to patulin has led to many investigations into the biological basis driving the toxicity of patulin. Nevertheless, the mechanisms through which mammalian cells resists patulin-mediated toxicity is poorly understood. Here, we show that loss of the Nrf1 transcription factor renders cells sensitive to the acute cytotoxic effects of patulin. Nrf1 deficiency leads to accumulation of ubiquitinated proteins and protein aggregates in response to patulin exposure. Nrf1 expression is induced by patulin, and activation of proteasome genes by patulin is Nrf1-dependent. These findings suggest the Nrf1 transcription factor plays a crucial role in modulating cellular stress response against patulin cytotoxicity.
              Cover page: The Nrf1 transcription factor is induced by patulin and protects against patulin cytotoxicity.
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2023)
              The NFE2L1 transcription factor (aka Nrf1) is a basic leucine zipper protein that performs a critical role in the cellular stress response pathway. Here, we characterized a novel variant of NFE2L1 referred to as NFE2L1-616. The transcript encoding NFE2L1-616 is derived from an intronic promoter, and it has a distinct first exon than other reported full-length NFE2L1 isoforms. The NFE2L1-616 protein constitutively localizes in the nucleus as it lacks the N-terminal amino acid residues that targets other full-length NFE2L1 isoforms to the endoplasmic reticulum. The expression level of NFE2L1-616 is lower than other NFE2L1 isoforms. It is widely expressed across different cell lines and tissues that were examined. NFE2L1-616 showed strong transcriptional activity driving luciferase reporter expression from a promoter containing antioxidant response element. Together, the results suggest that NFE2L1-616 variant can function as a positive regulator in the transcriptional regulation of NFE2L1 responsive genes.
                Cover page: Characterization of NFE2L1-616, an isoform of nuclear factor-erythroid-2 related transcription factor-1 that activates antioxidant response element-regulated genes.
                • Article
                • Peer Reviewed
                UC Irvine Previously Published Works (2022)
                The NFE2L1 transcription factor (also known as Nrf1 for nuclear factor erythroid 2-related factor-1) is a broadly expressed basic leucine zipper protein that performs a critical role in the cellular stress response pathway. Here, we identified a heterozygous nonsense mutation located in the last exon of the gene that terminates translation prematurely, resulting in the production of a truncated peptide devoid of the carboxyl-terminal region containing the DNA-binding and leucine-zipper dimerization interface of the protein. Variant derivatives were well expressed in vitro, and they inhibited the transactivation function of wild-type proteins in luciferase reporter assays. Our studies suggest that this dominant-negative effect of truncated variants is through the formation of inactive heterodimers with wild-type proteins preventing the expression of its target genes. These findings suggest the potential role of diminished NFE2L1 function as an explanation for the developmental delay, hypotonia, hypospadias, bifid scrotum, and failure to thrive observed in the patient.
                  Cover page: A novel nonsense variant in the NFE2L1 transcription factor in a patient with developmental delay, hypotonia, genital anomalies, and failure to thrive
                  • Article
                  • Peer Reviewed
                  UC Irvine Previously Published Works (2012)
                    Cover page: Characterization of Nrf1b, a Novel Isoform of the Nuclear Factor-Erythroid-2 Related Transcription Factor-1 That Activates Antioxidant Response Element-Regulated GenesCreative Commons 'BY' version 4.0 license
                    • Article
                    • Peer Reviewed
                    UC Irvine Previously Published Works (2016)
                    The NRF2 (also known as NFE2L2) transcription factor is a critical regulator of genes involved in defense against oxidative stress. Previous studies suggest thatNrf2plays a role in adipogenesisin vitro, and deletion of theNrf2gene protects against diet-induced obesity in mice. Here, we demonstrate that resistance to diet-induced obesity inNrf2(-/-)mice is associated with a 20-30% increase in energy expenditure. Analysis of bioenergetics revealed thatNrf2(-/-)white adipose tissues exhibit greater oxygen consumption. White adipose tissue showed a >2-fold increase inUcp1gene expression. Oxygen consumption is also increased nearly 2.5-fold inNrf2-deficient fibroblasts. Oxidative stress induced by glucose oxidase resulted in increasedUcp1expression. Conversely, antioxidant chemicals (such asN-acetylcysteine and Mn(III)tetrakis(4-benzoic acid)porphyrin chloride) and SB203580 (a known suppressor ofUcp1expression) decreasedUcp1and oxygen consumption inNrf2-deficient fibroblasts. These findings suggest that increasing oxidative stress by limitingNrf2function in white adipocytes may be a novel means to modulate energy balance as a treatment of obesity and related clinical disorders.
                      Cover page: Increased Energy Expenditure, Ucp1 Expression, and Resistance to Diet-induced Obesity in Mice Lacking Nuclear Factor-Erythroid-2-related Transcription Factor-2 (Nrf2)*
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