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 modulation of vascular smooth muscle cells (VSMCs) from the quiescent phenotype to the proliferative and migratory phenotype is a critical event in the pathogenesis of atherosclerosis. To-date several growth factors, including platelet-derived growth factor, PDGF, have been shown to induce VSMC proliferation and migration. To further understand the mechanism of PDGF-induced VSMC activation, quiescent human coronary artery SMC were treated with PDGF, and the genes that displayed transcriptional changes within 3 and 8 h were identified using differential display RT-PCR, real-time PCR, nucleotide sequencing and bioinformatics. Eleven genes that were highly upregulated or down-regulated at 3 and/or 8 h by PDGF, designated growth-factor regulated VSMC genes (GRSG1-11), were analyzed. GRSG5 and GRSG9-1 were identified as cortactin and cytochrome c oxidase subunit II, respectively. The remaining nine GRSGs were novel. GRSG3, 4, 5 and 9-2 showed wide tissue distribution whereas GRSG10-1, 10-2, and 11 were tissue specific. Cortactin was localized by immunohistochemical staining to the neointima and fibrous cap of human coronary artery atherosclerotic plaques. Domain analysis of open reading frames suggest that the novel GRSGs may participate in signaling, metabolic, translational or migrational processes during PDGF-induced VSMC activation.
Mol Cell Biochem 2006 Jan
PMID:mRNA differential display identification of vascular smooth muscle early response genes regulated by PDGF. 1632 58

The SMC protein complexes safeguard genomic integrity through their functions in chromosome segregation and repair. The chromosomal localization of the budding yeast Smc5/6 complex determined here reveals that the complex works specifically on the duplicated genome in differently regulated pathways. The first controls the association to centromeres and chromosome arms in unchallenged cells, the second regulates the association to DNA breaks, and the third directs the complex to the chromosome arm that harbors the ribosomal DNA arrays. The chromosomal interaction pattern predicts a function that becomes more important with increasing chromosome length and that the complex's role in unchallenged cells is independent of DNA damage. Additionally, localization of Smc6 to collapsed replication forks indicates an involvement in their rescue. Altogether this shows that the complex maintains genomic integrity in multiple ways, and evidence is presented that the Smc5/6 complex is needed during replication to prevent the accumulation of branched chromosome structures.
Mol Cell 2006 Jun 23
PMID:Chromosomal association of the Smc5/6 complex reveals that it functions in differently regulated pathways. 1679 45

Adiponectin was revealed to have anti-atherogenic and anti-inflammatory properties and has been recently found to stimulate angiogenesis in vivo and in vitro. However, the role of adiponectin in endothelial differentiation remains unclear. The objective of this study was to investigate whether adiponectin can promote peripheral CD14(+) monocytes differentiation into endothelial cells (ECs). Human peripheral blood CD14(+) monocytes were cultured with or without adiponectin (10 microg/ml) for 10 days. Adiponectin significantly promoted EC morphology formation from CD14(+) monocytes. By flow cytometery analysis, cells treated with adiponection substantially increased mean fluorescence intensity of vascular endothelial growth factor receptor-2 (VEGFR-2) and endothelial nitric oxide synthase (eNOS), two specific endothelial markers, by 49.2 % and 53.9 %, respectively, as compared to control cells. By real time PCR analysis, the mRNA level of eNOS in adiponectin-treated cells was also increased by 31.9 % of that of the control cells. However, the mRNA levels of calponin and SMMHC, two specific SMC markers, in adiponectin-treated cells were decreased by 81.1 % and 79.7 % of that of the control cells, respectively. These data demonstrated that adiponectin could promote endothelial differentiation from peripheral blood CD14(+) monocytes by morphology change, upregulation of EC markers and downregulation of SMC markers. Adiponectin-promoted EC differentiation may contribute to vascular healing and angiogenesis.
J Cell Mol Med
PMID:Adiponectin promotes endothelial cell differentiation from human peripheral CD14+ monocytes in vitro. 1679 11

Oxygen causes perinatal pulmonary dilatation. Although fetal pulmonary artery smooth muscle cells (PA SMC) normally respond to an acute increase in oxygen (O2) tension with a decrease in cytosolic calcium ([Ca2+]i), an acute increase in O2 tension has no net effect on [Ca(2+)](i) in PA SMC derived from lambs with chronic intrauterine pulmonary hypertension (PHTN). The present experimental series tests the hypothesis that an acute increase in O2 tension decreases capacitative calcium entry (CCE) in normal, but not hypertensive, fetal PA SMC. PA SMC were isolated from late-gestation fetal lambs after either ligation of the ductus arteriosus (PHTN) or sham (control) operation at 127 days gestation. PA SMC were isolated from the distal PA (>or=4th generation) and maintained under hypoxic conditions ( approximately 25 Torr) in primary culture. After fura 2 loading, apparent [Ca2+]i in PA SMC was determined as the ratio of 340- to 380-nm fluorescence intensity. Under both hypoxic and normoxic conditions, cyclopiazonic acid (CPA) increased [Ca2+]i more in PHTN than in control PA SMC. CCE was determined in PA SMC under hypoxic and normoxic conditions, after superfusion with zero extracellular Ca2+ and intracellular store depletion with CPA, followed by superfusion with Ca2+-containing solution, in the presence of the voltage-operated calcium channel blockade. CCE was increased in PHTN compared with control PA SMC under conditions of both acute and sustained normoxia. Transient receptor potential channel gene expression was greater in control compared with PHTN PA SMC. PHTN may compromise perinatal pulmonary vasodilation, in part, by modulating PA SMC CCE.
Am J Physiol Lung Cell Mol Physiol 2007 Apr
PMID:Chronic intrauterine pulmonary hypertension increases capacitative calcium entry in fetal pulmonary artery smooth muscle cells. 1715 1

The presence of immune cells is important for plaque destabilization. Disturbed flow conditions were shown to enhance the recruitment of circulating immune cells. Thus, we analyzed in 54 atherosclerotic carotid plaques the frequency of different immune cells, HLA-DR, chemokines, and chemokine receptors, comparing the upstream with the downstream plaque shoulder. The presence of neovascularization and intraplaque hemorrhages was investigated by CD34 immunostaining and Mallory's iron stain. Immunohistochemical analyses were performed to detect smooth muscle cells (SMC: actin), macrophages (CD68), T cells (CD3), dendritic cells (DC: fascin), mature DC (CD83), and the expression of HLA-DR, chemokine receptors (CCR-2, CCR-6), and chemokines (MCP-1, MIP-3alpha). Significantly more SMC were detected downstream than upstream (p<0.001). In contrast, significantly more macrophages (p=0.01), DC (p=0.03), mature DC (p=0.007), and a higher expression of HLA-DR (p=0.004), CCR-2 (p=0.002), CCR-6 (p<0.001), MCP-1 (p=0.04), and MIP-3alpha (p=NS) were observed upstream than downstream. Immune cells were strongly associated with neovascularization. The abundance of SMC downstream provides an explanation for distal plaque growth. Enhanced recruitment of immune cells through neovessels into the upstream shoulder might be contributing to plaque destabilization.
Exp Mol Pathol 2007 Jun
PMID:Accumulation of immune cells and high expression of chemokines/chemokine receptors in the upstream shoulder of atherosclerotic carotid plaques. 1722 20

The majority of familial pulmonary arterial hypertension (PAH) cases are caused by mutations in the type 2 bone morphogenetic protein receptor (BMPR2). However, less than one-half of BMPR2 mutation carriers develop PAH, suggesting that the most important function of BMPR2 mutation is to cause susceptibility to a "second hit." There is substantial evidence from the literature implicating dysregulated inflammation, in particular the cytokine IL-6, in the development of PAH. We thus hypothesized that the BMP pathway regulates IL-6 in pulmonary tissues and conversely that IL-6 regulates the BMP pathway. We tested this in vivo using transgenic mice expressing an inducible dominant negative BMPR2 in smooth muscle, using mice injected with an IL-6-expressing virus, and in vitro using small interfering RNA (siRNA) to BMPR2 in human pulmonary artery smooth muscle cells (PA SMC). Consistent with our hypothesis, we found upregulation of IL-6 in both the transgenic mice and in cultured PA SMC with siRNA to BMPR2; this could be abolished with p38(MAPK) inhibitors. We also found that IL-6 in vivo caused a twofold increase in expression of the BMP signaling target Id1 and caused increased BMP activity in a luciferase-reporter assay in PA SMC. Thus we have shown both in vitro and in vivo a complete negative feedback loop between IL-6 and BMP, suggesting that an important consequence of BMPR2 mutations may be poor regulation of cytokines and thus vulnerability to an inflammatory second hit.
Am J Physiol Lung Cell Mol Physiol 2007 Jun
PMID:Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. 1732 83

The circular Escherichia coli chromosome is organized by bidirectional replication into two equal left and right arms (replichores). Each arm occupies a separate cell half, with the origin of replication (oriC) at mid-cell. E. coli MukBEF belongs to the ubiquitous family of SMC protein complexes that play key roles in chromosome organization and processing. In mukBEF mutants, viability is restricted to low temperature with production of anucleate cells, reflecting chromosome segregation defects. We show that in mukB mutant cells, the two chromosome arms do not separate into distinct cell halves, but extend from pole to pole with the oriC region located at the old pole. Mutations in topA, encoding topoisomerase I, do not suppress the aberrant positioning of chromosomal loci in mukB cells, despite suppressing the temperature-sensitivity and production of anucleate cells. Furthermore, we show that MukB and the oriC region generally colocalize throughout the cell cycle, even when oriC localization is aberrant. We propose that MukBEF initiates the normal bidirectional organization of the chromosome from the oriC region.
Mol Microbiol 2007 Sep
PMID:MukB colocalizes with the oriC region and is required for organization of the two Escherichia coli chromosome arms into separate cell halves. 1782 28

Platelet-activating factor (PAF) is implicated in pathogenesis of chronic hypoxia-induced pulmonary hypertension in some animal models and in neonates. Effects of chronic hypoxia on PAF receptor (PAF-R) system in fetal pulmonary vasculature are unknown. We investigated the effect of chronic high altitude hypoxia (HAH) in fetal lambs [pregnant ewes were kept at 3,801 m (12,470 ft) altitude from approximately 35 to 145 days gestation] on PAF-R-mediated effects in the pulmonary vasculature. Age-matched controls were kept at sea level. Intrapulmonary arteries were isolated, and smooth muscle cells (SMC-PA) were cultured from HAH and control fetuses. To determine presence of pulmonary vascular remodeling, lung tissue sections were subjected to morphometric analysis. Percentage medial wall thickness was significantly increased (P < 0.05) in arteries at all levels in the HAH lambs. PAF-R protein expression studied by immunocytochemistry and Western blot analysis on lung tissue SMC-PA demonstrated greater PAF-R expression in HAH lambs. PAF-R binding (femtomoles per 10(6) cells) in HAH SMC-PA was 90.3 +/- 4.08 and 66% greater than 54.3 +/- 4.9 in control SMC-PA. Pulmonary arteries from HAH fetuses synthesized >3-fold PAF than vessels from controls. Compared with controls SMC-PA of HAH lambs demonstrated 139% and 40% greater proliferation in 10% FBS alone and with 10 nM PAF, respectively. Our data demonstrate that exposure of ovine fetuses to HAH will result in significant upregulation of PAF synthesis, PAF-R expression, and PAF-R-mediated effects in pulmonary arteries. These findings suggest that increased PAF-R protein expression and increased PAF binding contribute to pulmonary vascular remodeling in these animals and may predispose them to persistent pulmonary hypertension after birth.
Am J Physiol Lung Cell Mol Physiol 2007 Dec
PMID:Role of platelet-activating factor in pulmonary vascular remodeling associated with chronic high altitude hypoxia in ovine fetal lambs. 1795 13

The SMC protein complexes play important roles in chromosome dynamics. The function of the SMC5-6 complex remains unclear, though it is involved in resolution of different DNA structures by recombination. We have now identified and characterized the four non-SMC components of the human complex and in particular demonstrated that the MAGEG1 protein is part of this complex. MAGE proteins play important but as yet undefined roles in carcinogenesis, apoptosis, and brain development. We show that, with the exception of the SUMO ligase hMMS21/hNSE2, depletion of any of the components results in degradation of all the other components. Depletion also confers sensitivity to methyl methanesulfonate. Several of the components are modified by sumoylation and ubiquitination.
Mol Cell Biol 2008 Feb
PMID:Identification of the proteins, including MAGEG1, that make up the human SMC5-6 protein complex. 1808 88

We engineered mutants into residues of SMC2 to dissect the role of ATPase function in the condensin complex. These residues are predicted to be involved in ATP binding or hydrolysis and in the Q-loop, which is thought to act as a mediator of conformational changes induced by substrate binding. All the engineered ATPase mutations resulted in lethality when introduced into SMC2 null cells. We found that ATP binding, but not hydrolysis, is essential to allow stable condensin association with chromosomes. How SMC proteins bind and interact with DNA is still a major question. Cohesin may form a ring structure that topologically encircles DNA. We examined whether condensin behaves in an analogous way to its cohesin counterpart, and we have generated a cleavable form of biologically active condensin with PreScission protease sites engineered into the SMC2 protein. This has allowed us to demonstrate that topological integrity of the SMC2-SMC4 heterodimer is not necessary for the stability of the condensin complex in vitro or for its stable association with mitotic chromosomes. Thus, despite their similar molecular organization, condensin and cohesin exhibit fundamental differences in their structure and function.
Mol Biol Cell 2008 Jul
PMID:Molecular and genetic analysis of condensin function in vertebrate cells. 1848 Apr 6


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