ubiquinone ubiquitin

1: Chem Biol Interact. 2005 May 30;153-154:137-46. Epub 2005 Apr 7. Related Articles, Links
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Functions and distribution of NQO1 in human bone marrow: potential clues to benzene toxicity.

Ross D.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Campus Box C238, Denver, CO 80262, USA. David.Ross@uchsc.edu

NADPH:quinone oxidoreductase 1 (NQO1) may perform multiple functions within the cell. It is known to detoxify benzene-derived quinones and generate antioxidant forms of ubiquinone and Vitamin E. Recently suggested roles for NQO1 which may have relevance for mechanisms underlying benzene toxicity include modulation of cellular redox balance, direct scavenging of superoxide, stabilization of p53 and stabilization of microtubules. The NQO1*2 polymorphism is a single nucleotide polymorphism, a C to T change at position 609 of the NQO1 cDNA coding for a proline to serine change at position 187 of the amino acid structure of the protein. The mutant NQO1*2 protein is rapidly degraded by the ubiquitin proteasomal system resulting in a lack of NQO1 protein in individuals carrying the NQO1*2/*2 genotype. The NQO1*2 polymorphism predisposes to benzene toxicity and to various forms of leukemias. NQO1-knockout animals demonstrate myeloid hyperplasia and increased benzene-induced hematotoxicity. NQO1 is not present in freshly isolated human bone marrow hematopoietic cells but can be induced by benzene metabolites. Increases in NQO1 were not observed in NQO1*2/*2 hematopoietic cells, presumably because of the instability of the NQO1*2 protein, suggesting that cells with this genotype would not benefit from any protective effects of NQO1. NQO1 is present in human bone marrow stroma and particularly in endothelial cells. Studies of the functions and distribution of NQO1 in human bone marrow may provide clues to mechanisms underlying benzene toxicity.

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PMID: 15935810 [PubMed – indexed for MEDLINE]


2: Res Nurs Health. 2004 Jun;27(3):174-84. Related Articles, Links
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Indomethacin and ibuprofen preserve gastrocnemius muscle mass in mice bearing the colon-26 adenocarcinoma.

McCarthy DO, Whitney P, Hitt A, Al-Majid S.

National Institute of Nursing Research, National Institutes of Health, 31 Center Drive, Rm. 5B13, Bethesda, MD 20892, USA.

Skeletal muscle wasting is a prominent feature of cancer cachexia and involves decreased muscle protein synthesis and increased activity of the ubiquitin-proteasome pathway of protein degradation. We report that both indomethacin and ibuprofen improved body weight and weight of the gastrocnemius muscle in tumor-bearing mice. Ibuprofen increased the soluble protein content of the muscle without affecting muscle levels of phosphorylated p70 S6 kinase, a ribosomal kinase involved in protein synthesis. Paradoxically, indomethacin increased levels of ubiquitin-conjugated proteins. Further study is needed to understand the mechanism of action by which indomethacin and ibuprofen preserve body weight and muscle mass in the tumor-bearing mice. The data suggest that ibuprofen may have beneficial effects in the treatment of cancer cachexia. Copyright 2004 Wiley Periodicals, Inc.

PMID: 15141370 [PubMed – indexed for MEDLINE]


3: FASEB J. 2004 Feb;18(2):350-2. Epub 2003 Dec 4. Related Articles, Links
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Combined cDNA array/RT-PCR analysis of gene expression profile in rat gastrocnemius muscle: relation to its adaptive function in energy metabolism during fasting.

de Lange P, Ragni M, Silvestri E, Moreno M, Schiavo L, Lombardi A, Farina P, Feola A, Goglia F, Lanni A.

Dipartimento di Scienze della Vita, Seconda Universita degli Studi di Napoli (SUN), Caserta, Italy.pieter.delange@unina2.it

We evaluated the effects of fasting on the gene expression profile in rat gastrocnemius muscle using a combined cDNA array and RT-PCR approach. Of the 1176 distinct rat genes analyzed on the cDNA array, 114 were up-regulated more than twofold in response to fasting, including all 17 genes related to lipid metabolism present on the membranes and all 10 analyzed components of the proteasome machinery. Only 7 genes were down-regulated more than twofold. On the basis of our analysis of genes on the cDNA array plus the data from our RT-PCR assays, the metabolic adaptations shown by rat gastrocnemius muscle during fasting are reflected by i) increased transcription both of myosin heavy chain (MHC) Ib (associated with type I fibers) and of at least three factors involved in the shift toward type I fibers [p27kip1, muscle LIM protein (MLP), cystein rich protein-2], of which one (MLP) has been shown to enhance the activity of MyoD, which would explain the known increase in the expression of skeletal muscle uncoupling protein-3 (UCP3); ii) increased lipoprotein lipase (LPL) expression, known to trigger UCP3 transcription, which tends, together with the first point, to underline the suggested role of UCP3 in mitochondrial lipid handling (the variations under the first point and this one have not been observed in mice, indicating a species-specific regulation of these mechanisms); iii) reduced expression of the muscle-specific coenzyme Q (CoQ)7 gene, which is necessary for mitochondrial CoQ synthesis, together with an increased expression of mitochondrial adenylate kinase 3, which inactivates the resident key enzyme for CoQ synthesis, 3-hydroxy-3-methylglutaryl CoA reductase (HMGR), the mRNA level for which fell during fasting; and iv) increased transcription of components of the proteasomal pathways involved in protein degradation/turnover.

PMID: 14656997 [PubMed – indexed for MEDLINE]


4: Histol Histopathol. 2003 Apr;18(2):509-17. Related Articles, Links
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Ubiquitinated inclusions and neuronal cell death.

Lang-Rollin I, Rideout H, Stefanis L.

Department of Neurology, Columbia University, New York, NY 10032, USA.

Ubiquitinated inclusions and selective neuronal cell death are considered the pathological hallmarks of Parkinson’s disease and other neurodegenerative diseases. Recent genetic, pathological and biochemical evidence suggests that dysfunction of ubiquitin-dependent protein degradation by the proteasome might be a contributing, if not initiating factor in the pathogenesis of these diseases. In neuronal cell culture models inhibition of the proteasome leads to cell death and formation of fibrillar ubiquitin and alpha-synuclein-positive inclusions, thus modeling some aspects of Lewy body diseases. The processes of inclusion formation and neuronal cell death share some common mechanisms, but can also be dissociated at a certain level.

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PMID: 12647802 [PubMed – indexed for MEDLINE]


5: Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):473-7. Epub 2003 Jan 6. Related Articles, Links
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Atpenins, potent and specific inhibitors of mitochondrial complex II (succinate-ubiquinone oxidoreductase).

Miyadera H, Shiomi K, Ui H, Yamaguchi Y, Masuma R, Tomoda H, Miyoshi H, Osanai A, Kita K, Omura S.

Department of Biomedical Chemistry, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.

Enzymes in the mitochondrial respiratory chain are involved in various physiological events in addition to their essential role in the production of ATP by oxidative phosphorylation. The use of specific and potent inhibitors of complex I (NADH-ubiquinone reductase) and complex III (ubiquinol-cytochrome c reductase), such as rotenone and antimycin, respectively, has allowed determination of the role of these enzymes in physiological processes. However, unlike complexes I, III, and IV (cytochrome c oxidase), there are few potent and specific inhibitors of complex II (succinate-ubiquinone reductase) that have been described. In this article, we report that atpenins potently and specifically inhibit the succinate-ubiquinone reductase activity of mitochondrial complex II. Therefore, atpenins may be useful tools for clarifying the biochemical and structural properties of complex II, as well as for determining its physiological roles in mammalian tissues.

PMID: 12515859 [PubMed – indexed for MEDLINE]


6: Biotechnol Prog. 2001 Nov-Dec;17(6):1137-44. Related Articles, Links
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Proteomic investigation of metabolic shift in mammalian cell culture.

Seow TK, Korke R, Liang RC, Ong SE, Ou K, Wong K, Hu WS, Chung MC.

Bioprocessing Technology Centre, National University of Singapore, Singapore.

Mammalian cells, under typical cultivation conditions, produce large quantities of lactate and ammonia that affect cell growth adversely and result in low cell concentration. Controlled nutrient feeding to maintain low concentrations of glucose and glutamine reduces metabolite production drastically, altering the metabolism of the cells. This metabolic shift results in higher cell concentration in continuous cultures and does not affect the specific productivity of the cells. We have taken a proteomics approach to investigate the differential protein expression with metabolic shift. Using two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS), we have found at least eight differentially expressed spots; two proteins were down-regulated, and the others were up-regulated with metabolic shift. These included metabolic enzymes, the brain form of phosphoglycerate mutase, which was down-regulated, and the precursor of the 23 kDa subunit of NADH-ubiquinone oxidoreductase, which was up-regulated. Another enzyme, the L1 isozyme of ubiquitin carboxyl-terminal hydrolase, which is involved in protein turnover and degradation, was also up-regulated in the metabolically altered cells. The remaining down-regulated spot had been identified as two isoforms of cytoplasmic actins, while three of the up-regulated spots were viral GAG polyproteins from various murine viruses. An unidentified protein was also up-regulated in the cells with altered metabolic state. This study shows the potential of using a proteomics approach in deciphering the intracellular changes in cells with physiological changes such as metabolism shift. The new insight into cell metabolism afforded by this analysis will greatly facilitate process optimization of continuous cell cultures.

PMID: 11735452 [PubMed – indexed for MEDLINE]


7: Biochem Biophys Res Commun. 2000 Sep 16;276(1):144-50. Related Articles, Links
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Inhibiting proteasomes in human HepG2 and LNCaP cells increases endogenous androgen receptor levels.

Sheflin L, Keegan B, Zhang W, Spaulding SW.

VA Western New York Healthcare System, State University of New York at Buffalo, Buffalo, New York 14215, USA.

Treating HepG2 cells with MG132 for 4 h to inhibit proteasomal activity increased androgen receptor immunoreactivity in two major bands with molecular weights of 102 and 110 kDa by 77% each (P < 0. 05). MG132 treatment also increased the overall level of polyubiquitinated proteins between 66 and 220 kDa by 140% (P < 0.05). Antiubiquitin immunoreactivity comigrating with the androgen receptor bands was also increased by MG132 treatment. Two other proteasome inhibitors, lactacystin and epoxomycin, caused similar increases in the androgen receptor in HepG2 cells. Proteosome-inhibition studies conducted in LNCaP cells also showed that the two major androgen receptor bands with molecular weights of 102 and 110 kDa were increased by 85 and 115%, respectively (P < 0. 05 for both) by MG132 treatment. Overall levels of polyubiquitinated proteins with molecular weights between 66 and 220 kDa increased 365%. Ubiquitin immunoreactivity comigrating with the androgen receptor bands was also significantly increased. Thus inhibiting proteasomes in two human androgen-responsive cell lines increases endogenous androgen receptor levels as well as androgen receptor-associated ubiquitin-modified immunoreactivity. The regulation of steady-state levels of endogenous androgen receptor by proteasomal degradation could be involved in its rapid turnover in the absence of ligand and would provide a mechanism for limiting androgen responses. A PEST sequence similar to one in the vitamin D receptor is present in the hinge region of all known mammalian androgen receptors, suggesting that it may function in proteasome-mediated androgen receptor turnover. Copyright 2000 Academic Press.

PMID: 11006097 [PubMed – indexed for MEDLINE]


8: Am J Physiol Heart Circ Physiol. 2000 Apr;278(4):H1084-90. Related Articles, Links
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Dietary coenzyme Q(10) supplement renders swine hearts resistant to ischemia-reperfusion injury.

Maulik N, Yoshida T, Engelman RM, Bagchi D, Otani H, Das DK.

Department of Surgery, University of Connecticut School of Medicine, Farmington, Connecticut 06030-1110, USA.

To examine whether nutritional supplementation of coenzyme Q(10) (CoQ(10)) can reduce myocardial ischemia-reperfusion injury, a group of swine was fed a regular diet supplemented with CoQ(10) (5 mg x kg(-1) x day(-1)) for 30 days. Another group of pigs that were fed a regular diet supplemented with placebo served as a control. After 30 days, isolated in situ pig hearts were prepared and hearts were perfused with a cardiopulmonary pump system. Each heart was subjected to 15 min of regional ischemia by snaring of the left anterior descending coronary artery, followed by 60 min of hypothermic cardioplegic global ischemia and 120 min of reperfusion. After the experiments were completed, myocardial infarct size was measured by triphenyltrazolium chloride staining methods. Postischemic left ventricular contractile function was better recovered in the CoQ(10) group than in the control group of pigs. CoQ(10)-fed pigs revealed less myocardial infarction and less creatine kinase release from the coronary effluent compared with control pigs. The experimental group also demonstrated a smaller amount of malonaldehyde in the coronary effluent and a higher content of the endogenous antioxidants ascorbate and thiol. Significant induction of the expression of ubiquitin mRNA was also found in the hearts of the CoQ(10)-fed group. The results of this study demonstrate that nutritional supplementation of CoQ(10) renders the hearts resistant to ischemia-reperfusion injury, probably by reducing the oxidative stress.

PMID: 10749701 [PubMed – indexed for MEDLINE]


9: J Biol Chem. 1999 Jun 18;274(25):18135-9. Related Articles, Links
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Bivalent inhibitor of the N-end rule pathway.

Kwon YT, Levy F, Varshavsky A.

Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.

The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. Ubr1p, the recognition (E3) component of the Saccharomyces cerevisiae N-end rule pathway, contains at least two substrate-binding sites. The type 1 site is specific for N-terminal basic residues Arg, Lys, and His. The type 2 site is specific for N-terminal bulky hydrophobic residues Phe, Leu, Trp, Tyr, and Ile. Previous work has shown that dipeptides bearing either type 1 or type 2 N-terminal residues act as weak but specific inhibitors of the N-end rule pathway. We took advantage of the two-site architecture of Ubr1p to explore the feasibility of bivalent N-end rule inhibitors, whose expected higher efficacy would result from higher affinity of the cooperative (bivalent) binding to Ubr1p. The inhibitor comprised mixed tetramers of beta-galactosidase that bore both N-terminal Arg (type 1 residue) and N-terminal Leu (type 2 residue) but that were resistant to proteolysis in vivo. Expression of these constructs in S. cerevisiae inhibited the N-end rule pathway much more strongly than the expression of otherwise identical beta-galactosidase tetramers whose N-terminal residues were exclusively Arg or exclusively Leu. In addition to demonstrating spatial proximity between the type 1 and type 2 substrate-binding sites of Ubr1p, these results provide a route to high affinity inhibitors of the N-end rule pathway.

PMID: 10364269 [PubMed – indexed for MEDLINE]


10: Acta Biol Hung. 1991;42(1-3):21-6. Related Articles, Links
The role of protein ubiquitination in neurodegenerative disease.

Mayer RJ, Lowe J, Landon M, McDermott H, Laszlo L.

Department of Biochemistry, University of Nottingham Medical School, Queen’s Medical Centre, U.K.

Ubiquitin immunocytochemistry with an antiserum which reacts with ubiquitin-protein conjugates demonstrates the presence of ubiquitinated proteins in filamentous inclusions found in neurones in the major human neurodegenerative diseases, i.e. Alzheimer’s disease, diffuse Lewy body disease, motor neurone disease. Ubiquitin immunohistochemistry has revolutionized the neuropathological diagnosis of dementia showing that diffuse Lewy body disease is not, as previously supposed, a rare cause of dementia. The filamentous inclusions in neurones in the human neurodegenerative diseases can be divided into at least two types based on recent immunocytochemical studies. We have shown that a ubiquitin-carboxyl terminal hydrolase is present in Lewy bodies but not in neurofibrillary tangles in Alzheimer’s disease. This observation is significant since it indicates that molecular pathological mechanisms in neurones in diffuse Lewy body disease are fundamentally different to Alzheimer’s disease. Ubiquitin-protein conjugates are also found in vacuoles in areas of granulovacuolar degeneration in hippocampal neurones in Alzheimer’s disease and in granulovacuoles in neurones of scrapie infected mouse brain. These locations suggest that ubiquitinated protein are present in the lysosome-related system of neurones. We have recently shown that ubiquitin-protein conjugates are indeed enriched some 12-fold in the lysosomes of normal fibroblasts and lymphocytes.

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PMID: 1668896 [PubMed – indexed for MEDLINE]

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