Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.9.3.1 (cytochrome oxidase)
 8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steroid hormones, which are ubiquitous regulators of physiologic processes, are produced primarily in the adrenals, gonads, and placenta. Each steroidogenic cell type produces different steroids due to cell-specific expression of various steroidogenic enzymes, but all steroidogenesis is initiated by P450scc, the mitochondrial enzyme that converts cholesterol to pregnenolone. We previously showed the unique segments of the P450scc promoter that are responsible for basal and cAMP-induced expression of this gene in the placenta are not employed for expression in the adrenal (C.C.D. Moore, D.W. Hum, and W.L. Miller, Mol. Endocrinol. 6, 2045-2058, 1992). We now show that sequences between -142 and -153 exhibit placental-specific activator activity. Sequences between -131 and -155 can confer activator activity to a 32-bp promoter from the thymidine kinase gene of herpes simplex virus in an orientation-independent fashion. Two protein complexes, termed IV and VII, interact specifically with DNA from -131 to -155. Mutating bases -142 to -151 abolishes formation of complex VII and partially inhibits complex IV, suggesting that the proteins forming these complexes bind neighboring segments of DNA. Mutating only two cytosines at bases 141 and 142 also eliminates the formation of complex VII and reduces the transcriptional activity of the activator by about 75-80%, indicating that complex VII is important for placental expression of P450scc. The sequence from -140 to -149 on the antisense strand resembles an NF-kappa B binding site. Antibodies to NF-kappa B subunit p50, but not to p52, p65, or c-Rel, will supershift some but not all of complex IV, whereas none of these antibodies interact with complex VII. A consensus NF-kappa B oligonucleotide does not form complex IV, suggesting that p50 interacts with the protein component, but not the DNA component of complex IV. Photoaffinity UV cross-linking yielded single bands of cross-linked DNA-protein complexes at approximately 85 kD for complex IV and approximately 70 kD for complex VII, indicating that separate proteins form complexes IV and VII. Southwestern blotting identified a single protein of 55 kD forming complex VII but did not identify the protein forming complex IV. Bandshifts and Southwestern blots with nuclear extracts from steroidogenic human placental JEG-3 cells and human adrenal NCI-H295 cells show that this 55-kD protein is found in placental but not adrenal cells. This 55-kD nuclear protein appears to be a trans-acting factor necessary for placental but not adrenal expression of P450scc.
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PMID:Characterization of placental transcriptional activation of the human gene for P450scc. 774 95

Activated microglia are implicated in the injury of neurones and macroglia both in vitro and in vivo. Here, we demonstrate that media conditioned by interferon-gamma treated microglia initially impair the metabolism of mouse cerebellar neurones grown in serum-free conditions without inducing cell death. Metabolic effects include inhibition of the ability of mitochondria to reduce 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and cytochrome oxidase activity. These effects are blocked by antibodies to tumour necrosis factor-alpha (TNFalpha), a cytokine produced by microglial activation, and they are not reproduced by media conditioned by resting microglia. The metabolic effects are evident for up to 24 h in vitro. More prolonged exposure, up to 48 h, results in TNFalpha dependent neuronal death as previously observed. Between 2 and 48 h TNFalpha present in media conditioned by interferon-gamma treated but not resting microglia is associated with nuclear factor kappa B (NF-kappaB) consensus sequence binding in paired mouse cerebellar neuronal cultures without affecting activation of the signal transducer and activator of transcription (STAT) transcription factor. Neuronal death can be accelerated by peptide blockade of the nuclear transport of NF-kappaB p52 subunit during exposure of cerebellar neurones to medium from interferon-gamma treated microglia. This toxicity is blocked by anti-TNFalpha antibody. Soluble factors released by activated microglia therefore contribute to neuronal dysfunction that is initially reversible but may culminate in neurotoxicity. Characterizing and manipulating these events in vivo theoretically provides an opportunity for neuroprotection in selected diseases affecting the central nervous system.
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PMID:Inhibition of tumour necrosis factor-alpha (TNFalpha)-induced NF-kappaB p52 converts the metabolic effects of microglial-derived TNFalpha on mouse cerebellar neurones to neurotoxicity. 1123 28