Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously demonstrated that the sphingolipid, sphingosylphosphocholine (SPC) increased DNA binding activity of AP-1 proteins accompanying cellular proliferation. Herein, the effects of SPC on DNA binding activity and transcription of the basic, helix-loop-helix, leucine zipper (bHLH-ZIP) proteins Myc, Max, and USF were investigated because they regulate genes involved in mitogenesis. E-box (CACGTG) DNA binding proteins were detected by electrophoretic mobility shift assays in nuclear extracts from Swiss 3T3 fibroblasts. The slowest migrating complex (complex I) increased within 1-3 min after treatment with SPC, remained elevated for 10 min, and increased again after 12 h. Complexes I and II contained USF-1 and USF-2 proteins, and complex I migrated similarly to recombinant USF-1 protein/DNA complex. Treatment of nuclear extracts with alkaline phosphatase decreased these complexes suggesting USF might be a phosphoprotein, post-translationally modified by SPC. max and usf-1 mRNA levels were unaffected by SPC treatment. In contrast, c-myc mRNA was rapidly elevated, reached maximum levels at 0.5-1 h, and showed an additional increase after 12 h, just preceding S phase. Thus, certain bHLH-ZIP transcription factors may be involved in cell growth regulation by SPC.
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PMID:The potent lipid mitogen sphingosylphosphocholine activates the DNA binding activity of upstream stimulating factor (USF), a basic helix-loop-helix-zipper protein. 950 45

We have identified a novel signaling pathway that leads to expression of matrix metalloproteinase-9 (MMP-9) in murine macrophages in response to the bacterial endotoxin, LPS. We showed that p38 kinase was essential for this induction and observed that LPS-induced MMP-9 expression was sensitive to rottlerin, a putative protein kinase Cdelta (PKCdelta) inhibitor. However neither infection with a retrovirus expressing a dominant negative mutant of PKCdelta nor down-regulation of PKCdelta by prolonged PMA treatment affected MMP-9 expression, thus excluding involvement of PKCdelta. Interestingly, LPS-induced MMP-9 expression and p38 kinase phosphorylation were shown to be suppressed by the antioxidant N-acetylcysteine and the flavoenzyme inhibitor diphenyleneiodonium chloride, but not by pyrrolidine dithiocarbamate, an NF-kappaB inhibitor. In addition, LPS was found to induce the production of mitochondrial reactive oxygen species (ROS) and this effect was rottlerin-sensitive, suggesting an inhibitory effect of rottlerin on mitochondrial ROS. LPS-induced MMP-9 expression and p38 kinase phosphorylation were also inhibited by rotenone, a specific inhibitor of mitochondrial complex I, supporting the role of mitochondrial ROS in LPS signaling to MMP-9. Finally, we showed that the ROS-p38 kinase cascade targets the transcription factor AP-1. Taken together, our findings identify a ROS-p38 kinase-AP-1 cascade as a novel pathway mediating LPS signaling to MMP-9 expression in macrophages.
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PMID:Lipopolysaccharide induces matrix metalloproteinase-9 expression via a mitochondrial reactive oxygen species-p38 kinase-activator protein-1 pathway in Raw 264.7 cells. 1555 94

Nonmelanoma skin cancer afflicts more than one million people in the U.S. annually, highlighting the need for more effective preventive regimens. We have investigated the ability of deguelin, a plant-derived rotenoid with cancer chemopreventive activity, to inhibit UVB-induced skin carcinogenesis with the SKh-1 mouse model. Topically-applied deguelin significantly inhibited the multiplicity of UVB-induced skin tumors, indicating potential as a human skin cancer chemopreventive agent. Mechanistic studies to determine the potential of deguelin to block a number of established UVB-induced molecular events yielded negative results [including UVB-induced AP-1 DNA binding, c-fos and TNFalpha mRNA induction, arachidonic acid release and UVB-induced phosphorylation of mTOR (Ser2448), akt (Ser473) and erk (Thr202/Tyr204)]. These results are of interest as they contradict a major hypothesis for the mode of action of deguelin, i.e., a general down regulation of signal transduction based on inhibition of NADH dehydrogenase and depletion of ATP levels. In the current work, however, deguelin was found to activate 5' AMP-activated kinase (AMPK), a protein that acts as a cellular energy sensor. This is the first report of a chemopreventive agent having this effect and suggests a possible role for AMPK in cancer chemoprevention.
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PMID:Effect of deguelin on UVB-induced skin carcinogenesis. 1604 63

This article shows that T cell activation-induced expression of the cytokines IL-2 and -4 is determined by an oxidative signal originating from mitochondrial respiratory complex I. We also report that ciprofloxacin, a fluoroquinolone antibiotic, exerts immunosuppressive effects on human T cells suppressing this novel mechanism. Sustained treatment of preactivated primary human T cells with ciprofloxacin results in a dose-dependent inhibition of TCR-induced generation of reactive oxygen species (ROS) and IL-2 and -4 expression. This is accompanied by the loss of mitochondrial DNA and a resulting decrease in activity of the complex I. Consequently, using a complex I inhibitor or small interfering RNA-mediated downregulation of the complex I chaperone NDUFAF1, we demonstrate that TCR-triggered ROS generation by complex I is indispensable for activation-induced IL-2 and -4 expression and secretion in resting and preactivated human T cells. This oxidative signal (H(2)O(2)) synergizes with Ca(2+) influx for IL-2/IL-4 expression and facilitates induction of the transcription factors NF-kappaB and AP-1. Moreover, using T cells isolated from patients with atopic dermatitis, we show that inhibition of complex I-mediated ROS generation blocks disease-associated spontaneous hyperexpression and TCR-induced expression of IL-4. Prolonged ciprofloxacin treatment of T cells from patients with atopic dermatitis also blocks activation-induced expression and secretion of IL-4. Thus, our work shows that the activation phenotype of T cells is controlled by a mitochondrial complex I-originated oxidative signal.
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PMID:Mitochondrial reactive oxygen species control T cell activation by regulating IL-2 and IL-4 expression: mechanism of ciprofloxacin-mediated immunosuppression. 2033 30

c-jun, which is overexpressed in a number of human cancers encodes a critical component of the AP-1 complex. c-jun has been shown to either induce or inhibit cellular apoptosis. Germ line deletion of both c-jun alleles is embryonically lethal. To determine the role of the endogenous c-jun gene in apoptosis, we performed mammary epithelial cell-targeted somatic deletion using floxed c-jun (c-jun(f/f)) conditional knockout mice. Laser capture microdissection demonstrated endogenous c-jun inhibits expression of apoptosis inducing genes and reactive oxygen species (ROS)-reducing genes (MnSOD, catalase). ROS have been implicated in apoptosis and undergo enzymatic elimination via MnSOD and CuZnSOD with further detoxification via catalase. c-jun-mediated survival was in part dependent on ROS production. c-jun-mediated repression of MnSOD and catalase occurred via mitochondrial complex I and NOX I. Collectively, these studies define a pivotal role of endogenous c-jun in promoting cell survival via maintaining mitochondrial integrity and expression of the key regulators of ROS production.
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PMID:C-jun inhibits mammary apoptosis in vivo. 2092 81