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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a recent study, we investigated the metabolism of 1alpha,25-dihydroxy-20-epi-vitamin D3 (1alpha,25(OH)2-20-epi-D3), a potent synthetic vitamin D3 analog in the isolated perfused rat kidney and proposed that the enhanced biological activity of 1alpha,25(OH)2-20-epi-D3 is in part due to its metabolism into stable bioactive intermediary metabolites derived via the C-24 oxidation pathway (Siu-Caldera et al. [1999] J. Steroid. Biochem. Mol. Biol. 71:111-121). It is now well established that 1alpha,25(OH)2D3 and its analogs are metabolized in target tissues not only via the C-24 oxidation pathway but also via the C-3 epimerization pathway. As the perfused rat kidney does not express the C-3 epimerization pathway, we could not identify other possible bioactive metabolites of 1alpha,25(OH)2-20-epi-D3 such as 1alpha,25(OH)2-20-epi-3-epi-D3, derived via the C-3 epimerization pathway. Therefore, we studied the metabolism of 1alpha,25(OH)2-20-epi-D3 in rat osteosarcoma cells (UMR 106) which express both the C-24 oxidation and the C-3 epimerization pathways. Our results indicate that 1alpha,25(OH)2-20-epi-D3 is metabolized in UMR 106 cells into several metabolites which included not only the previously known metabolites of the C-24 oxidation pathway but also three new metabolites which were labeled as metabolites X, Y1, and Y2. Metabolite X was unequivocally identified as 1alpha,25(OH)2-20-epi-3-epi-D3. Even though definite structure identification of the metabolites, Y1 and Y2 was not achieved in our present study, we determined that the metabolite Y1 is produced from 1alpha,25(OH)2-20-epi-D3 and the metabolite Y2 is produced from 1alpha,25(OH)2-20-epi-3-epi-D3. We also noted the production of both 1alpha,25(OH)2-20-epi-3-epi-D3 and the two metabolites Y1 and Y2 in different rat osteosarcoma cells (ROS 17/2.8) which express only the C-3 epimerization pathway but not the C-24 oxidation pathway. Furthermore, we investigated the metabolism of 1alpha,25(OH)2-20-epi-D3 in the isolated perfused rat kidney in an earlier study. The results of this study indicated that the rat kidney unlike rat osteosarcoma cells did not produce either 1alpha,25(OH)2-20-epi-3-epi-D3 or the metabolites Y1 and Y2. Thus, it appears that the metabolites Y1 and Y2, like 1alpha,25(OH)2-20-epi-3-epi-D3, are produced only in specific tissues. Preliminary biological activity of each new metabolite is assessed by measuring its ability to generate VDR-mediated gene transcription. 1alpha,25(OH)2-20-epi-3-epi-D3 was found to be almost equipotent to 1alpha,25(OH)2-20-epi-D3 while the metabolites, Y1 and Y2 were found to be less active. The metabolite Y1 when compared to the metabolite Y2 has higher biological activity and its potency is almost equal to 1alpha,25(OH)2D3. In summary, we report for the first time tissue specific metabolism of 1alpha,25(OH)2-20-epi-D3 into several bioactive metabolites which are derived not only via the previously established C-24 oxidation and C-3 epimerization pathways but also via a new pathway. (c) 2001 Wiley-Liss, Inc.
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PMID:Tissue specific metabolism of 1alpha,25-dihydroxy-20-epi-vitamin D3 into new metabolites with significant biological activity: studies in rat osteosarcoma cells (UMR 106 and ROS 17/2.8). 1150 Sep 38

Spatial and temporal expression and regulation of the antioxidant enzymes, glutathione peroxidase (GSH-Px), glutathione disulfide reductase (GSSG-Rd) may be important in determining cell-specific susceptibility to embryotoxicants. Creation of tissue-specific ontogenies for antioxidant enzyme activities during development is an important first step in understanding regulatory relationships. Early organogenesis-stage embryos were grouped according to the somite number (GD 9-13), and fetuses were evaluated by gestational day (GD 14-21). GSH-Px activities in the visceral yolk sac (VYS) increased on consecutive days from GD 9 to GD 13, representing a 5.7-fold increase during this period of development. GSH-Px activities in VYS decreased after GD 13, ultimately constituting a 37% decrease at GD 21. Head, heart, and trunk specific activities generally increased from GD 9 to GD 13 albeit not to the same magnitude as detected in the VYS. GSSG-Rd activities showed substantial increases in the VYS from GD 9 to GD 13, 6.3-fold and decreased thereafter to 50% by GD 21. The greatest changes in enzyme activities were noted in the period between GD 10 and GD 11, where the embryo establishes an active cardiovascular system and begins to convert to aerobic metabolism. Generally, from GD 14-21, embryonic organ GSH-Px and GSSG-Rd activities either remained constant or increased as gestation progressed. These studies suggest the importance of the VYS in dealing with ROS and protecting the embryo. Furthermore, understanding the consequences of lower antioxidant activities during organogenesis may help to pinpoint periods of teratogenic susceptibility to xenobiotics and increased oxygen.
J Biochem Mol Toxicol 2001
PMID:Spatial and temporal ontogenies of glutathione peroxidase and glutathione disulfide reductase during development of the prenatal rat. 1167 48

Recently, a procedure for detecting ROS-sensitive proteins that contain active cysteine residues was devdoped. The method is based on the fact that biotin-conjugated iodoacetamide (BIAM) and ROS competitively and selectively react with the active cysteine residues in ROS-sensitive proteins. To investigate the role of ROS in cervical cancer, BIAM labeling on cytosolic proteins in normal and cancer tissues was performed, respectively. The BIAM labeling proteins are separated by 2-dimensional electrophoresis, and then identified by MALDI-TOF mass analysis. ROS-sensitive protein is identified as creatine kinase B containing cysteine residue in active center. Activity of creatine kinase B in normal tissue is higher than that of oxidized form in cervical cancer tissues. The result suggests that ROS play an important role in metabolic regulation in cervical cancer cells. However, molecular mechanisms that ROS and creatine kinase B are integrated into a physiological signal leading to the cellular transformation remain to be elucidated.
Mol Cells 2001 Dec 31
PMID:Creatine kinase B is a target molecule of reactive oxygen species in cervical cancer. 1180 44

We have investigated protein kinase C (PKC) regulation by 1,25-(OH)2D3 in the rat osteosarcoma cell line ROS 17/2.8 since previous reports have implicated PKC in the 1,25-(OH)2D3-mediated regulation of osteocalcin gene expression (J. Biol. Chem. 267 (1992) 12562; Endocrinology 136 (1995) 5685). Here we report that 1,25-(OH)2D3 increased PKCalpha, but not PKCbetaI, epsilon or zeta, levels in the nuclear fraction in a time-dependent manner. Unlike PMA, 1,25-(OH)2D3 did not alter the association of any of the expressed PKC isoenzymes with the plasma membrane. Treatment with 20 nM 1,25-(OH)2D3 for 15 min, 30 min, 1 h and 24 h increased PKCalpha levels in the nuclear fraction by 2.3- to 2.6-fold. Nuclear PKCalpha expression was also increased with doses of 1,25-(OH)2D3 as low as a 0.05 nM. 1,25-(OH)2D3-mediated stabilization of osteocalcin mRNA (Arch. Biochem. Biophys. 332 (1996) 142) was inhibited with bisindolylmaleimide treatment, suggesting that PKCalpha may be involved in the 1,25-(OH)2D3-mediated regulation of osteocalcin gene expression.
Mol Cell Endocrinol 2002 Feb 25
PMID:1,25-Dihydroxyvitamin D3 selectively translocates PKCalpha to nuclei in ROS 17/2.8 cells. 1191 60

One-day-old chicks were reared using diets differing in their vitamin E and/or selenium content. The purpose of this research was to detect any possible imbalance in the antioxidant defense system, which could be related to development of nutritional pancreatic atrophy. Mitochondrial membranes from animals deficient in both nutrients, or just vitamin E, submitted to peroxidizability 'in vitro' had the production of TBARS greatly enhanced. Measurements of the 2-GSH/GSSG ratio suggested that selenium and vitamin E, the latter in higher magnitude, were responsible for maintenance of the reducing capacity of the cell. Enzymatic defense systems against oxidative stress were also studied. The results indicated that the total antioxidant enzymatic activity of pancreatic cells was not sufficient to scavenge all the ROS generated in the nutritionally deficient animals. The present study suggests that nutritional deficiency of selenium and/or vitamin E generates one imbalance between pro-oxidant and antioxidant systems in chicken pancreas, leading to oxidative stress and pancreatic atrophy.
Comp Biochem Physiol B Biochem Mol Biol 2002 Apr
PMID:Role of antioxidant systems in induced nutritional pancreatic atrophy in chicken. 1192 94

Inherited retinal dystrophies are the main causes of progressive visual impairment often leading to blindness. They represent a clinically and genetically heterogenous group of disorders. Continuously increasing body of evidence links retinal dystrophies to mutations in numerous genes. These genes code for retinal proteins of various function (phototransduction, visual cycle, transcription factors, structural and metabolic functions). Mutations in the gene coding for photoreceptor specific guanylate cyclase type 1, ROS-GC1, were found to be the cause for the type 1 Leber's congenital amaurosis (LCAI) and cone-rod dystrophy type 6 (CORD6). The LCA1-linked mutations are distributed over almost the entire ROS-GCI coding sequence but the CORD6-linked mutations are restricted to three positions, E786, R787 and T788, located within the putative ROS-GC1 dimerization domain. A linkage between the biochemical effect of the mutation and its phenotypic manifestation was provided for only one LCA1 mutation, F514S. This was followed by biochemical analyses of the consequences of the CORD6-causing mutations. Here, an overview on the existing results and a discussion of the possible physiological implications are presented.
Mol Cell Biochem 2002 Jan
PMID:Retinal diseases linked with photoreceptor guanylate cyclase. 1195 88

Two membrane bound guanylate cyclases are expressed in vertebrate photoreceptor cells. They serve a key function in photoreceptor physiology as they synthesize the intracellular transmitter of photoexcitation guanosine 3',5'-cyclic monophosphate (cGMP). Both cyclases named ROS-GC1 and ROS-GC2 form a subclass of membrane bound cyclases and differ in many aspects from hormone peptide receptor guanylate cyclases. One unique feature is their regulation by three small Ca2+-binding proteins called GCAPs. These regulatory proteins sense changes in the cytoplasmic Ca2+-concentration [Ca2+] during illumination and activate ROS-GCs when the [Ca2+] decreases below the value in a dark adapted cell of 500-600 nM. Recent work has identified the target regions of GCAP-1 in ROS-GC1. In addition to GCAPs several other proteins including aktin, tubulin, a glutamic-acid-rich protein and a GTPase accelerating protein (RGS9) were found to interact with ROS-GC1 and probably form a multiprotein complex.
Mol Cell Biochem 2002 Jan
PMID:Photoreceptor specific guanylate cyclases in vertebrate phototransduction. 1195

Age-related changes in cardiovascular function and structure in healthy adult volunteer community dwelling subjects (from 20 to 85 years) is remarkable for changes in pump function [impaired left ventricular (LV) ejection reserve capacity manifest by a reduced ejection fraction and accompanied by diminished cardioacceleration, LV dilation at end diastole and an altered diastolic filling pattern] and increased vascular afterloading. There is also evidence for a reduction in the number of cardiac myocytes with advancing age. Subcellular changes with aging (best understood in rodents) include certain regulatory factors of excitation-contraction-relaxation coupling (i.e. calcium handling), modulation by adrenergic receptor (AR) stimulation, and changes in the generation and sensitivity to the damaging effects of ROS. Coordinated changes in gene expression and/or protein function with aging result in a prolonged action potential (AP), Ca(i) transient, and contraction. L-type Ca(2+) current (I(Ca)) inactivates more slowly, and outwardly-directed K(+) currents are reduced, and likely contribute to AP-prolongation. The rate of Ca(2+) sequestration by the sarcoplasmic reticulum (SR) decreases in the senescent myocardium, in part underlying the prolonged Ca(i) transient. An age-associated reduction in transcription of the SERCA2 gene, coding for the SR Ca(2+) pump, accounts in part for a decrease in the SR pump site density. The contractile response to both beta(1)-AR and beta(2)-AR stimulation diminishes with aging due to decreased adrenergic augmentation of I(Ca), and thus the Ca(i) transient, in senescent vs. young hearts. The age-associated reduction in the postsynaptic response of myocardial cells to beta(1)-AR stimulation appears to be due to multiple changes in molecular and biochemical receptor coupling and post-receptor mechanisms. An increased basal production of ROS is paralleled by increased ROS-sensitivity, markers of chronic ROS damage and mitochondrial functional decline. Overall, these changes lead to a diminished (but not necessarily exhausted) capacity of the heart to adapt to physiological or pathological stress with advancing age.
Comp Biochem Physiol A Mol Integr Physiol 2002 Aug
PMID:Perspectives on mammalian cardiovascular aging: humans to molecules. 1209 57

In this study, we investigated the effects of proteasome inhibibors (MG132 and lactacystin) on interleukin (IL)-8 induction. In human epithelial A549 cells, MG132 and lactacystin induced IL-8 release within the range of 0.1-30 microM. The effect of MG132 resulted from IL-8 gene transcription and was blocked by PD 98059, but was unaffected by GF109203X, Ro 31-8220, or SB 203580. Mutational analysis of the 5' flanking region of the IL-8 gene revealed that activator protein (AP)-1-binding element, but not that element responsive to nuclear factor (NF)-IL-6 or NF-kappaB, was necessary for MG132 stimulation. Consistent with this, MG132 and lactacystin increased the DNA-binding and reporter activities of AP-1, but reduced cytokine-elicited kappaB activation. Moreover, AP-1 stimulation was associated with increased extracellular signal-related kinase (ERK), mitogen-activated protein/ERK kinase (MEK), and c-Jun N-terminal kinase (JNK) phosphorylation, whereas IL-8 activity was sensitive to the dominant-negative mutants of JNK1, JNK2, SEK, ASK, ERK2, and Ras, but not those of MEKK1, TAK, and p38 mitogen-activated protein kinase. In addition, activations of the IL-8 gene and AP-1 by MG132 and lactacystin were inhibited by GSH and NAC. Herein we present a novel action of proteasome inhibitors, possibly through ROS production, of targeting the upstream signaling molecules, ERK and JNK, which leads to AP-1 activation and IL-8 gene expression.
Am J Respir Cell Mol Biol 2002 Aug
PMID:Proteasome inhibitors stimulate interleukin-8 expression via Ras and apoptosis signal-regulating kinase-dependent extracellular signal-related kinase and c-Jun N-terminal kinase activation. 1215 16

Cell signaling pathways may be initiated by environmental particulates by indirect mechanisms such as elaboration of reactive oxygen or nitrogen species (ROS/RNS) or directly upon contact of particulates with the plasma membrane and uptake by epithelial or mesothelial cells. Research in the last few years has mainly addressed cell signaling cascades leading to activation of the redox-sensitive transcription factors, nuclear factor kappa-B (NF-kappaB), and activator protein-1 (AP-1). The activation of these transcription factors may be linked to increases in gene expression controlling cell injury or apoptosis, proliferation and/or cell survival, and inflammatory cytokines. Here, we provide an overview of the MAPK signaling pathways and their activation by asbestos, specifically the role of ROS, receptor-dependent and independent activation via the epidermal growth factor receptor (EGFR), and strategies for proving causal relationships between these pathways and changes in epithelial cell phenotype linked to disease causation.
Mol Cell Biochem
PMID:Role of mitogen-activated protein kinases (MAPK) in cell injury and proliferation by environmental particulates. 1216 23


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