A5058983683- Genomics, phytochemicals, and oxidative stress
- Glutathione Transferases and Polymorphisms
- Mitochondrial Function and Pathology
- Adipose Tissue and Metabolism
- Air Quality and Health Impacts
- Epigenetics and DNA Methylation
- Redox biology and oxidative stress
- Sulfur Compounds in Biology
- Cancer-related molecular mechanisms research
- Plant Stress Responses and Tolerance
- RNA Research and Splicing
- Estrogen and related hormone effects
- Autophagy in Disease and Therapy
- Metabolism, Diabetes, and Cancer
- Bioactive Compounds and Antitumor Agents
- Psoriasis: Treatment and Pathogenesis
- Genetics and Neurodevelopmental Disorders
- Animal Genetics and Reproduction
- Drug Transport and Resistance Mechanisms
- Plant Genetic and Mutation Studies
- IL-33, ST2, and ILC Pathways
- Liver Disease Diagnosis and Treatment
- Childhood Cancer Survivors' Quality of Life
- MicroRNA in disease regulation
- Nitrogen and Sulfur Effects on Brassica
Fred Hutch Cancer Center
2020-2024
University of Pittsburgh
2011-2021
Cancer Research Center
2020
Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa
2020
Osaka University
1990-2012
Johns Hopkins University
2002-2011
Child and Family Research Institute
2010
University of British Columbia
2010
Johns Hopkins Medicine
2005
University of Tsukuba
1999-2004
Transcription factor Nrf2 is essential for the antioxidant responsive element (ARE)-mediated induction of phase II detoxifying and oxidative stress enzyme genes. Detailed analysis differential activity displayed in transfected cell lines ultimately led to identification a new protein, which we named Keap1, that suppresses transcriptional by specific binding its evolutionarily conserved amino-terminal regulatory domain. The closest homolog Keap1 Drosophila actin-binding protein called Kelch,...
Coordinate induction of phase 2 proteins and elevation glutathione protect cells against the toxic carcinogenic effects electrophiles oxidants. All inducers react covalently with thiols at rates that are closely related to their potencies. Inducers disrupt cytoplasmic complex between actin-bound protein Keap1 transcription factor Nrf2, thereby releasing Nrf2 migrate nucleus where it activates antioxidant response element (ARE) genes accelerates transcription. We cloned, overexpressed,...
Induction of a family phase 2 genes encoding for proteins that protect against the damage electrophiles and reactive oxygen intermediates is potentially major strategy reducing risk cancer chronic degenerative diseases. Many are regulated by upstream antioxidant response elements (ARE) targets leucine zipper transcription factor Nrf2. Under basal conditions, Nrf2 resides mainly in cytoplasm bound to its cysteine-rich, Kelch domain-containing partner Keap1, which itself anchored actin...
Abstract Background: Transcription factor Nrf2 regulates the expression of a set detoxifying and anti‐oxidant enzyme genes. Several lines evidence suggest that electrophiles reactive oxygen species liberate from its cytoplasmic repressor Keap1 provoke accumulation in nucleus. To elucidate molecular mechanisms as to how is activated by inducers, we examined cytoplasmic‐nuclear shuttling turnover Nrf2. Results: We found rapidly degraded through proteasome pathway, while cause nuclear...
The Nrf2 (nuclear factor E2 p45-related 2) transcription responds to diverse oxidative and electrophilic environmental stresses by circumventing repression Keap1, translocating the nucleus, activating cytoprotective genes. responses provide protection against chemical carcinogenesis, chronic inflammation, neurodegeneration, emphysema, asthma sepsis in murine models. regulates expression of a plethora genes that detoxify oxidants electrophiles repair or remove damaged macromolecules, such as...
Enzyme inducers such as 3H-1,2-dithiole-3-thione (D3T) enhance the detoxication of environmental carcinogens and protect against neoplasia. The putative molecular sensor for is Keap1, a sulfhydryl-rich protein that sequesters transcription factor Nrf2 in cytoplasm. Expression these enzymes blunted nrf2-deficient mice; moreover, mice are more sensitive to carcinogenesis, protective actions dithiolethiones lost with nrf2 disruption. Hepatic gene expression profiles were examined by...
The dynamin-related guanosine triphosphatase Drp1 mediates the division of mitochondria and peroxisomes. To understand in vivo function Drp1, complete tissue-specific mouse knockouts were generated. Drp1-null mice die by embryonic day 11.5. This lethality is not likely caused gross energy deprivation, as cells showed normal intracellular adenosine triphosphate levels. In support role organelle division, formed extensive networks, peroxisomes elongated fibroblasts. Brain-specific ablation...
Transcription factor Nrf2 regulates basal and inducible expression of phase 2 proteins that protect animal cells against the toxic effects electrophiles oxidants. Under conditions, is sequestered in cytoplasm by Keap1, a multidomain, cysteinerich protein bound to actin cytoskeleton. Keap1 acts both as repressor transactivation sensor inducers. Electrophiles oxidants disrupt Keap1–Nrf2 complex, resulting nuclear accumulation Nrf2, where it enhances transcription genes via common upstream...
Proteasomes degrade damaged proteins formed during oxidative stress, thereby promoting cell survival.Neurodegenerative and other age-related disorders are associated with reduced proteasome activity.We show herein that expression of most subunits 20S 19S proteasomes, which collectively assemble the 26S proteasome, was enhanced up to threefold in livers mice following treatment dithiolethiones, act as indirect antioxidants.Subunit protein levels activity were coordinately increased.No...
The NF-E2 p45-related factor 2 (NRF2) and the aryl hydrocarbon receptor (AHR) are transcription factors controlling pathways modulating xenobiotic metabolism. AHR has recently been shown to affect Nrf2 expression. Conversely, this study demonstrates that NRF2 regulates expression of Ahr subsequently modulates several downstream events signaling cascade, including (i) transcriptional control metabolism genes Cyp1a1 Cyp1b1 (ii) inhibition adipogenesis in mouse embryonic fibroblasts (MEFs)....
The mechanisms by which deregulated nuclear factor erythroid-2-related 2 (NRF2) and kelch-like ECH-associated protein 1 (KEAP1) signaling promote cellular proliferation tumorigenesis are poorly understood. Using an integrated genomics ¹³C-based targeted tracer fate association (TTFA) study, we found that NRF2 regulates miR-1 miR-206 to direct carbon flux toward the pentose phosphate pathway (PPP) tricarboxylic acid (TCA) cycle, reprogramming glucose metabolism. Sustained activation of in...
Mitochondria divide and fuse continuously, the balance between these two processes regulates mitochondrial shape. Alterations in dynamics are associated with neurodegenerative diseases. Here we investigate physiological cellular functions of division postmitotic neurons using vivo vitro gene knockout for protein Drp1. When mouse Drp1 was deleted Purkinje cells cerebellum, tubules elongated due to excess fusion, became large spheres oxidative damage, accumulated ubiquitin mitophagy markers,...
Significance Considering that Alzheimer’s disease (AD) is a chronic progressing over long period of time, even slight increase BACE1 expression may have profound effect on Aβ accumulation. We describe previously unknown mechanism negatively regulates and BACE1-AS demonstrate its pivotal role in the progression Tau pathologies cognitive impairment two mouse models AD. Given recent failures clinical trials using enzymatic inhibitors BACE1, it critical to explore alternative approaches such as...
Induction of the phase 2 response, a major cellular reaction to oxidative/electrophile stress depends on protein triad: actin-tethered Keap1 that binds Nrf2. Inducers react with releasing Nrf2 for nuclear translocation and activation antioxidant response element (ARE), which regulates genes. The primary sensors inducers are certain uniquely reactive cysteine thiols Keap1. Recombinant murine contains 0.9 zinc atoms per monomer as determined by inductively coupled plasma-optical emission...
The cell survival pathway mediated by the transcription factor Nrf2 facilitates tissue regeneration promoting Notch1 signaling.
Nuclear factor erythroid-2 related 2 (Nrf2), a redox-sensitive transcription factor, regulates the expression of antioxidant enzymes and several anti-apoptotic proteins, which confer cytoprotection against oxidative stress apoptosis. Constitutive activation Nrf2 in lung cancer cells promotes tumorigenicity contributes to chemoresistance by upregulation glutathione, thioredoxin, drug efflux pathways involved detoxification electrophiles broad spectrum drugs. In this study, we show that...