Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The small Maf basic leucine zipper (bZIP) proteins MafF, MafG and MafK, while modest in size, have emerged as crucial regulators of mammalian gene expression. Intriguingly, small Mafs do not contain an obvious transcriptional activation domain. However, previously perceived as "mere" partner molecules conferring DNA binding specificity to complexes with larger bZIP proteins, such as the CNC family member Nrf2, it has become clear that small Maf proteins are essential and dynamically regulated transcription factors. Current data suggest stringent control of small Maf protein function through transcriptional and post-translational mechanisms. Initial gene targeting experiments revealed considerable functional redundancy among small Maf proteins in vivo. This was not unexpected, due to the high level of homology among the three small Mafs. Nevertheless, further studies showed that these transcription factors have critical roles in various cellular processes, including stress signaling, hematopoiesis, CNS function and oncogenesis. Recent data provide a possible link between small Maf-mediated transcription and the inflammatory response.
J Mol Biol 2008 Feb 29
PMID:Small Maf proteins in mammalian gene control: mere dimerization partners or dynamic transcriptional regulators? 1820 22

Prothymosin alpha (ProTalpha) is a highly conserved protein in vertebrates that possesses a number of biological functions. One of these functions of ProTalpha is the ability to enhance antioxidant defence system of a cell via its interaction with Keap1 protein. Keap1 is a repressor of Nrf2, a transcription factor responsible for activation of genes that code for defensive proteins. While bound to Nrf2, Keap1 exports Nrf2 from the nucleus to the cytoplasm and, being adaptor protein for ubiquitin ligase, promotes ubiquitination of Nrf2 and its subsequent degradation by 26S proteasome. ProTalpha and Nrf2 compete for interaction with Keap1, therefore ProTalpha is able to liberate Nrf2 from complex with Keap1 and hence contribute to Nrf2-dependent transcription. Here we were interested in elucidating possible consequences for ProTalpha of its interaction with Keap1. We have shown that, despite ProTalpha interaction with Keap1, ProTalpha is a stable protein. In contrast to Nrf2 ProTalpha was not subjected to Keap-dependent ubiquitination, degradation and export from the nucleus. Furthermore, ubiquitination of ProTalpha was undetectable even when Keap1 and ubiquitin were overexpressed. It appears that ProTalpha contribution to Nrf2-dependent transcription is accomplished via the increase of free Nrf2 rather then the increase of total intracellular amount of Nrf2.
Mol Biol (Mosk)
PMID:[Prothyomosin alpha interaction with KEAP1 doesn't lead to prothymosin alpha ubiquination and degradation]. 1824 May 69

Keap1 and Cul3 constitute a unique ubiquitin E3 ligase that degrades Nrf2, a key activator of cytoprotective genes. Upon exposure to oxidants/electrophiles, the enzymatic activity of this ligase complex is inhibited and the complex fails to degrade Nrf2, resulting in the transcriptional activation of Nrf2 target genes. Keap1 possesses several reactive cysteine residues that covalently bond with electrophiles in vitro. To clarify the functional significance of each Keap1 cysteine residue under physiological conditions, we established a transgenic complementation rescue model. The transgenic expression of mutant Keap1(C273A) and/or Keap1(C288A) protein in Keap1 null mice failed to reverse constitutive Nrf2 activation, indicating that cysteine residues at positions 273 and 288 are essential for Keap1 to repress Nrf2 activity in vivo. In contrast, Keap1(C151S) retained repressor activity and mice expressing this molecule were viable. Mouse embryonic fibroblasts from Keap1(C151S) transgenic mice displayed decreased expression of Nrf2 target genes both before and after an electrophilic challenge, suggesting that Cys151 is important in facilitating Nrf2 activation. These results demonstrate critical roles of the cysteine residues in vivo in maintaining Keap1 function, such that Nrf2 is repressed under quiescent conditions and active in response to oxidants/electrophiles.
Mol Cell Biol 2008 Apr
PMID:Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. 1826 4

Curcumin is the active ingredient in the traditional herbal remedy and dietary spice turmeric (Curcuma longa). Curcumin has a surprisingly wide range of beneficial properties, including anti-inflammatory, antioxidant, chemopreventive and chemotherapeutic activity. The pleiotropic activities of curcumin derive from its complex chemistry as well as its ability to influence multiple signaling pathways, including survival pathways such as those regulated by NF-kappaB, Akt, and growth factors; cytoprotective pathways dependent on Nrf2; and metastatic and angiogenic pathways. Curcumin is a free radical scavenger and hydrogen donor, and exhibits both pro- and antioxidant activity. It also binds metals, particularly iron and copper, and can function as an iron chelator. Curcumin is remarkably non-toxic and exhibits limited bioavailability. Curcumin exhibits great promise as a therapeutic agent, and is currently in human clinical trials for a variety of conditions, including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis and Alzheimer's disease.
Cell Mol Life Sci 2008 Jun
PMID:Curcumin: from ancient medicine to current clinical trials. 1832 53

Mammalian hibernation is associated with wide variation in heart rate, blood flow, and oxygen delivery to tissues and is used as a model of natural ischemia/reperfusion. In non-hibernators, ischemia/reperfusion is typically associated with oxidative stress but hibernators seem to deal with potential oxidative damage by enhancing antioxidant defenses in an anticipatory manner. The present study assesses the role of the Nrf2 transcription factor in the regulation of antioxidant defenses during hibernation. Nrf2 mRNA and protein expression were enhanced in selected organs of 13-lined ground squirrels, Spermophilus tridecemlineatus during hibernation. Furthermore, Nrf2 protein in heart was elevated by 1.4-1.5 fold at multiple stages over a torpor-arousal bout including during entry, long term torpor, and early arousal. Levels returned to euthermic values when squirrels were fully aroused in interbout. Protein levels of selected downstream target genes under Nrf2 control were also measured via immunoblotting over the torpor-arousal cycle in heart. Cu/Zn superoxide dismutase and aflatoxin aldehyde reductase levels increased significantly during entry into torpor and then gradually declined falling to control levels or below in fully aroused animals. Heme oxygenase-1 also showed the same trend. This suggests a role for Nrf2 in regulating the antioxidant defenses needed for hibernation success. Heart nrf2 was amplified by PCR and sequenced. The deduced amino acid sequence showed high identity with the sequence from other mammals but with selected unique substitutions (e.g., proline residues at positions 111 and 230) that might be important for conformational stability of the protein at near 0 degrees C body temperatures in the torpid state.
Mol Cell Biochem 2008 May
PMID:Expression of Nrf2 and its downstream gene targets in hibernating 13-lined ground squirrels, Spermophilus tridecemlineatus. 1832 1

Cellular protection against oxidative and electrophile toxicities is provided by two types of small-molecule antioxidants: (i) direct antioxidants, which are redox active, short-lived, are sacrificed in the process of their antioxidant actions and need to be replenished or regenerated, and may evoke pro-oxidant effects; and (ii) indirect antioxidants, that may or may not be redox active. Indirect antioxidants activate the Keap1/Nrf2/ARE pathway resulting in transcriptional induction of a battery of cytoprotective proteins (also known as phase 2 enzymes) that act catalytically, are not consumed, have long half-lives, and are unlikely to evoke pro-oxidant effects. These protective systems are involved in a complex functional interplay, such that many cytoprotective proteins participate in the synthesis and/or regeneration of direct antioxidants, whereas some direct antioxidants are required for the catalytic functions of cytoprotective proteins. Importantly, many inducers of cytoprotective proteins have been isolated from edible plants, e. g., sulforaphane from broccoli and curcumin from turmeric. Both are pleiotropic agents with multiple biological activities that could collectively contribute to their protective effects in various animal studies, including models of carcinogenesis, hypertension, neuronal and retinal damage. In addition to inducing cytoprotective proteins, molecules like curcumin which contain Michael acceptor functionalities (olefins or acetylenes conjugated to electron withdrawing groups) and phenolic hydroxyl groups can scavenge directly and potently oxygen- and nitrogen-centered reactive intermediates. Such bifunctional antioxidants can play a dual protective role by: (i) scavenging hazardous oxidants directly and instantaneously, and (ii) inducing cytoprotective enzymes that in turn function to resolve the consequences of hazardous processes that are already in progress, and to ensure long-term protection against subsequent challenges.
Mol Nutr Food Res 2008 Jun
PMID:Direct and indirect antioxidant properties of inducers of cytoprotective proteins. 1832 72

Glutathione (GSH) is a ubiquitous intracellular peptide with diverse functions that include detoxification, antioxidant defense, maintenance of thiol status, and modulation of cell proliferation. GSH is synthesized in the cytosol of all mammalian cells in a tightly regulated manner. The major determinants of GSH synthesis are the availability of cysteine, the sulfur amino acid precursor, and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL). GCL is composed for a catalytic (GCLC) and modifier (GCLM) subunit and they are regulated at multiple levels and at times differentially. The second enzyme of GSH synthesis, GSH synthase (GS) is also regulated in a coordinated manner as GCL subunits and its up-regulation can further enhance the capacity of the cell to synthesize GSH. Oxidative stress is well known to induce the expression of GSH synthetic enzymes. Key transcription factors identified thus far include Nrf2/Nrf1 via the antioxidant response element (ARE), activator protein-1 (AP-1) and nuclear factor kappa B (NFkappaB). Dysregulation of GSH synthesis is increasingly being recognized as contributing to the pathogenesis of many pathological conditions. These include diabetes mellitus, pulmonary fibrosis, cholestatic liver injury, endotoxemia and drug-resistant tumor cells. Manipulation of the GSH synthetic capacity is an important target in the treatment of many of these disorders.
Mol Aspects Med
PMID:Regulation of glutathione synthesis. 1860 45

Nrf2 is the key transcription factor regulating the antioxidant response. Nrf2 signaling is repressed by Keap1 at basal condition and induced by oxidative stress. Keap1 is recently identified as a Cullin 3-dependent substrate adaptor protein. A two-sites binding "hinge & latch" model vividly depicts how Keap1 can efficiently present Nrf2 as substrate for ubiquitination. Oxidative perturbation can impede Keap1-mediated Nrf2 ubiquitination but fail to disrupt Nrf2/Keap1 binding. Nrf2 per se is a redox-sensitive transcription factor. A new Nrf2-mediated redox signaling model is proposed based on these new discoveries. Free floating Nrf2 protein functions as a redox-sensitive probe. Keap1 instead functions as a gate keeper to control the availability of Nrf2 probes and thus regulates the overall sensitivity of the redox signaling.
Mol Carcinog 2009 Feb
PMID:Molecular mechanisms of Nrf2-mediated antioxidant response. 1861 99

Excitotoxicity mediated by glutamate receptors may underlay the pathology of several neurologic diseases. Considering that oxidative stress is central to excitotoxic damage, in this study we sought to analyze if the transcription factor Nrf2, guardian of redox homeostasis, might be targeted to prevent kainate-induced neuron death. Hippocampal slices from Nrf2 knockout mice exhibited increased oxidative stress and cell death compared to those of control mice in response to kainate, as determined with the redox sensitive probes 2,7-dichlorodihydrofluorescein diacetate (H(2)DCFAC) and propidium iodide and lactate dehydrogenase release, respectively, therefore demonstrating a role of Nrf2 in antioxidant protection against excitotoxicity. In the hippocampus of mice intraperitoneally injected with kainate we observed a rapid activation of Akt, inhibition of GSK-3beta and translocation of Nrf2 to the nucleus, but after 4 h Akt was inactive, GSK-3beta was active and Nrf2 was mostly cytosolic, therefore extending our previous studies which indicate that GSK-3beta excludes Nrf2 from the nucleus. Lithium, a GSK-3beta inhibitor, promoted Nrf2 transcriptional activity towards an Antioxidant-Response-Element (ARE) luciferase reporter and cooperated with sulforaphane (SFN) to induce this reporter and to increase the protein levels of heme oxygenase-1 (HO-1), coded by a representative ARE-containing gene. Conversely, ARE activation by SFN was attenuated by over-expression of active GSK-3beta. Finally, combined treatment with SFN and lithium attenuated oxidative stress and cell death in kainate-treated hippocampal slices of wild type mice but not Nrf2 null littermates. Our findings identify the axis GSK-3beta/Nrf2 as a pharmacological target in prevention of excitotoxic neuronal death.
Mol Cell Neurosci 2008 Sep
PMID:Functional interference between glycogen synthase kinase-3 beta and the transcription factor Nrf2 in protection against kainate-induced hippocampal cell death. 1861 45

Nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates the up-regulation of cytoprotective genes via the antioxidant response element (ARE). In the pathogenesis of Alzheimer's disease (AD) current evidence supports the role of oxidative stress. Considering the protective role of Nrf2 against oxidative injury, we studied Nrf2 and Nrf2-ARE target genes in transgenic AD mice and tested whether Nrf2 could confer neuroprotection against amyloid-beta peptides (Abeta). Nrf2-ARE pathway was attenuated in APP/PS1 transgenic mouse brain at the time of Abeta deposition. Boosting the activity of the Nrf2-ARE pathway by tert-butylhydroquinone treatment or adenoviral Nrf2 gene transfer protected against Abeta toxicity. This neuroprotection was associated with increased expression of Nrf2 target genes and reduced phosphorylation of p66Shc, a marker of increased susceptibility for oxidative stress. The findings suggest that the Nrf2-ARE pathway may be impaired in AD and that induction of the Nrf2-ARE defence mechanism may prevent or delay AD-like pathology.
Mol Cell Neurosci 2008 Nov
PMID:Nuclear factor erythroid 2-related factor 2 protects against beta amyloid. 1870 2


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