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 insulin/relaxin peptide family includes insulin, IGFs, relaxin1-3, INSL3/RLF, INSL4, INSL5/RIF2 and INSL6/RIF1, many without functional characterization. Based on analysis of transgenic phenotypes and phylogenetic profiling, we have discovered that two orphan leucine-rich repeat-containing G protein-coupled receptors, LGR7 and LGR8, are cognate receptors for relaxin whereas INSL3 is a specific ligand for LGR8. With the identification of the relaxin receptors, it is now possible to investigate specific cells and tissues that are responsive to relaxin in diverse physiological and pathological conditions as well as to develop agonists and antagonists for LGR7 and LGR8 as therapeutics to treat different labor disorders. Furthermore, future functional characterization of the specificity of these pluripoentent receptors with peptide ligands could lead to the understanding of related orphan ligands and receptors.
Mol Cell Endocrinol 2003 Apr 28
PMID:Relaxin signaling in reproductive tissues. 1277 Jul 46

ADAM15 (named for a disintegrin and metalloprotease 15, metargidin) is a membrane-anchored glycoprotein that has been implicated in cell-cell or cell-matrix interactions and in the proteolysis of molecules on the cell surface or extracellular matrix. To characterize the potential roles of ADAM15 during development and in adult mice, we analyzed its expression pattern by mRNA in situ hybridization and generated mice carrying a targeted deletion of ADAM15 (adam15(-/-) mice). A high level of expression of ADAM15 was found in vascular cells, the endocardium, hypertrophic cells in developing bone, and specific areas of the hippocampus and cerebellum. However, despite the pronounced expression of ADAM15 in these tissues, no major developmental defects or pathological phenotypes were evident in adam15(-/-) mice. The elevated levels of ADAM15 in endothelial cells prompted an evaluation of its role in neovascularization. In a mouse model for retinopathy of prematurity, adam15(-/-) mice had a major reduction in neovascularization compared to wild-type controls. Furthermore, the size of tumors resulting from implanted B16F0 mouse melanoma cells was significantly smaller in adam15(-/-) mice than in wild-type controls. Since ADAM15 does not appear to be required for developmental angiogenesis or for adult homeostasis, it may represent a novel target for the design of inhibitors of pathological neovascularization.
Mol Cell Biol 2003 Aug
PMID:Potential role for ADAM15 in pathological neovascularization in mice. 1289 35

The coagulation factor V Leiden mutation was reported to be a significant (10.7%) risk factor for pre-term deliveries. It is also well known that a portion (10%) of very low birth weight premature babies develop advanced retinopathy of prematurity (ROP) which is a leading cause of blindness in children. However, the relationship between the Leiden mutation and development of advanced ROP is not known. In order to understand this relationship as well as genetic contribution to ROP, in this study, we have analyzed 100 pre-term infants with advanced ROP (stage 4B/5), 20 term babies with a clinically similar disease called familial exudative vitreoretinopathy (FEVR) and 16 normal babies from four different ethnic backgrounds. Our extensive analysis has identified a heterozygous Leiden mutation in four patients (4%) with advanced ROP and in one patient (5%) with sporadic FEVR. DNA sequence analysis has further confirmed this base change as well as heterozygosity. However, the frequency observed in the patients analyzed in our study is lower than reported frequency in the general population (5.4%). Therefore, statistically factor V mutation on its own is not a major risk factor for the above two disorders. However, it may be associated with other additive factors as might be expected for a complex genetic trait.
Int J Mol Med 2003 Oct
PMID:Factor V Leiden mutation (R506Q) and the risk of advanced retinopathy of prematurity. 1296 21

We hypothesize that poly(ADP-ribose) polymerase (PARP) activation is an important mechanism in the oxidative stress-related development of diabetic retinopathy. In the experiments reported here, we evaluated if: a) PARP activation is present in the retina in short-term diabetes; and b) PARP inhibitors, 3-aminobenzamide and 1,5-isoquinolinediol, counteract diabetes- and hypoxia-induced retinal VEGF formation. In vivo studies were performed in control and streptozotocin-diabetic rats treated with/without 3-aminobenzamide or 1,5-isoquinolinediol (30 and 3 mg/kg per day, intraperitoneally, for 2 weeks after 2 weeks of diabetes). In vitro studies were performed in human retinal pigment epithelial cells exposed to normoxia or hypoxia with/without 3-aminobenzamide and 1,5-isoquinolinediol at 200 and 2 micro M. Retinal immunostaining for poly(ADP-ribose) was increased and NAD concentration reduced in diabetic rats, and both variables were corrected by PARP inhibitors. Retinal VEGF protein (ELISA, immunohistochemistry), but not mRNA (ribonuclease protection assay) abundance, was increased in diabetic rats, and this increase was corrected by both 3-aminobenzamide and 1,5-isoquinolinediol. PARP inhibitors did not affect retinal glucose, sorbitol pathway intermediates or lipid peroxidation in diabetic rats. Hypoxia caused a several-fold increase in both VEGF-mRNA and protein in retinal pigment epithelial cells. VEGF mRNA overexpression was only slighly blunted by PARP inhibitors whereas VEGF protein was corrected. In conclusion, PARP is involved in diabetes- and hypoxia-induced VEGF production at post-transcriptional level, downstream from the sorbitol pathway activation and oxidative stress. The results justify studies of PARP inhibitors in models of retinopathy of prematurity and diabetic retinopathy.
Int J Mol Med 2004 Jul
PMID:Poly(ADP-ribose) polymerase inhibitors counteract diabetes- and hypoxia-induced retinal vascular endothelial growth factor overexpression. 1520 16

Angiotensin II, the effector peptide of the renin-angiotensin system (RAS), has potent growth factor properties in a variety of organs. In the retina, a complete RAS exists, with components residing in the vasculature, neurons and glia. There is increasing interest in a pathogenetic role for angiotensin II in ischaemic retinopathies such as diabetic retinopathy and retinopathy of prematurity. In these situations, the retinal RAS becomes activated and stimulates growth factors such as vascular endothelial growth factor, which contribute to vascular leakage, pericyte migration, angiogenesis and fibrosis. Blockade of the RAS, with either angiotensin-converting enzyme (ACE) inhibitors or antagonists selective for angiotensin type 1 (AT1) and angiotensin type 2 (AT2) receptors, attenuates many of the vascular abnormalities that develop in diabetic retinopathy and retinopathy of prematurity. Eagerly awaited are the findings of the Diabetic Retinopathy Candesartan Trial (DIRECT), evaluating the effects of AT1 receptor antagonism in patients with different stages of diabetic retinopathy. This review examines the role of the RAS in diabetic retinopathy and retinopathy of prematurity, and the potential of RAS blockade as a treatment strategy for these vision-threatening diseases.
Expert Rev Mol Med 2004 Jul 23
PMID:Diabetes and retinal vascular disorders: role of the renin-angiotensin system. 1538 97

Oscillation regulates a wide variety of processes ranging from chemotaxis in Dictyostelium through segmentation in vertebrate development to circadian rhythms. Most studies on the molecular mechanisms underlying oscillation have focused on processes requiring a rhythmic change in gene expression, which usually exhibit a periodicity of >10 min. Mechanisms that control oscillation with shorter periods (<10 min), presumably independent of gene expression changes, are poorly understood. Oscillatory pollen tube tip growth provides an excellent model to investigate such mechanisms. It is well established that ROP1, a Rho-like GTPase from plants, plays an essential role in polarized tip growth in pollen tubes. In this article, we demonstrate that tip-localized ROP1 GTPase activity oscillates in the same frequency with growth oscillation, and leads growth both spatially and temporally. Tip growth requires the coordinate action of two ROP1 downstream pathways that promote the accumulation of tip-localized Ca2+ and actin microfilaments (F-actin), respectively. We show that the ROP1 activity oscillates in a similar phase with the apical F-actin but apparently ahead of tip-localized Ca2+. Furthermore, our observations support the hypothesis that the oscillation of tip-localized ROP activity and ROP-dependent tip growth in pollen tubes is modulated by the two temporally coordinated downstream pathways, an early F-actin assembly pathway and a delayed Ca2+ gradient-forming pathway. To our knowledge, our report is the first to demonstrate the oscillation of Rho GTPase signaling, which may be a common mechanism underlying the oscillation of actin-dependent processes such as polar growth, cell movement, and chemotaxis.
Mol Biol Cell 2005 Nov
PMID:Oscillatory ROP GTPase activation leads the oscillatory polarized growth of pollen tubes. 1614 45

The Third International Symposium on Retinopathy of Prematurity (ROP) was convened with the aim of cross fertilizing the horizons of basic and clinical scientists with an interest in the pathogenesis and management of infants with ROP. Ten speakers in the clinical sciences and ten speakers in the basic sciences were recruited on the basis of their research to provide state of the art talks. The meeting was held November 9, 2003 immediately prior to the American Academy of Ophthalmology meeting; scholarships were provided for outreach to developing countries and young investigators. This review contain the summaries of the 20 platform presentations prepared by the authors and the abstracts of presented posters. Each author was asked to encapsulate the current state of understanding, identify areas of controversy, and make recommendations for future research. The basic science presentations included insights into the development of the human retinal vasculature, animal models for ROP, growth factors that affect normal development and ROP, and promising new therapeutic approaches to treating ROP like VEGF targeting, inhibition of proteases, stem cells, ribozymes to silence genes, and gene therapy to deliver antiangiogenic agents. The clinical presentations included new insights into oxygen management, updates on the CRYO-ROP and ETROP studies, visual function in childhood following ROP, the neural retina in ROP, screening for ROP, management of stage 3 and 4 ROP, ROP in the third world, and the complications of ROP in adult life. The meeting resulted in a penetrating exchange between clinicians and basic scientists, which provided great insights for conference attendees. The effect of preterm delivery on the normal cross-talk of neuroretinal and retinal vascular development is a fertile ground for discovering new understanding of the processes involved both in normal development and in retinal neovascular disorders. The meeting also suggested promising potential therapeutic interventions on the horizon for ROP.
Mol Vis 2006 May 23
PMID:Proceedings of the Third International Symposium on Retinopathy of Prematurity: an update on ROP from the lab to the nursery (November 2003, Anaheim, California). 1673 95

Small guanine nucleotide binding proteins of the Rho family called ROP play a crucial role as regulators of signal transduction in plants. They participate in pathways that influence growth and development, and the adaptation of plants to various environmental situations. As members of the Ras superfamily, ROPs function as molecular switches cycling between a GDP-bound 'off' and a GTP-bound 'on' state in a strictly regulated manner. Latest research provided fascinating new insights into ROP regulation by novel guanine nucleotide exchange factors, unconventional GTPase activating proteins, and guanine nucleotide dissociation inhibitors, which apparently organize localized ROP activation. Important progress has also been made concerning signaling components upstream and downstream of the ROP cycle involving receptor-like serine/threonine kinases and effectors that can manipulate cytoskeletal dynamics, intracellular calcium levels, H2O2 production and further cellular targets. This review outlines the fast developing knowledge on ROP GTPases highlighting their specific features, regulation and roles in a cellular signaling context.
Cell Mol Life Sci 2006 Nov
PMID:ROPs in the spotlight of plant signal transduction. 1693 55

Our knowledge of the genetic control of wood formation (i.e., secondary growth) is limited. Here, we present a novel approach to unraveling the gene network regulating secondary xylem development in Arabidopsis, which incorporates complementary platforms of comparative-transcriptome analyses such as "digital northern" and "digital in situ" analysis. This approach effectively eliminated any genes that are expressed in either non-stem tissues/organs ("digital northern") or phloem and non-vascular regions ("digital in situ"), thereby identifying 52 genes that are upregulated only in the xylem cells of secondary growth tissues as "core xylem gene set". The proteins encoded by this gene set participate in signal transduction, transcriptional regulation, cell wall metabolism, and unknown functions. Five of the seven signal transduction-related genes represented in the core xylem gene set encode the essential components of ROP (Rho-related GTPase from plants) signaling cascade. Furthermore, the analysis of promoter sequences of the core xylem gene set identified a novel cis-regulatory element, ACAAAGAA. The functional significances of this gene set were verified by several independent experimental and bioinformatics methods.
Mol Genet Genomics 2006 Dec
PMID:Global comparative transcriptome analysis identifies gene network regulating secondary xylem development in Arabidopsis thaliana. 1696 62

ROPs or RACs are plant Rho-related GTPases implicated in the regulation of a multitude of signaling pathways that function at the plasma membrane by virtue of posttranslational lipid modifications. The relationship between ROP activation status and membrane localization has not been established. Here we demonstrate that endogenous ROPs, as well as a transgenic His(6)-green fluorescent protein (GFP)-AtROP6 fusion protein, were partitioned between Triton X-100-soluble and -insoluble membranes. In contrast, an activated His(6)-GFP-Atrop6(CA) mutant protein accumulated exclusively in detergent-resistant membranes. GDP induced accumulation of ROPs in Triton-soluble membranes, whereas GTPgammaS induced accumulation of ROPs in detergent-resistant membranes. Recombinant wild-type and constitutively active AtROP6 isoforms were purified from Arabidopsis plants, and their lipids were cleaved and analyzed by gas chromatography-coupled mass spectrometry. In Triton-soluble membranes, wild-type AtROP6 was only prenylated, primarily by geranylgeranyl. The activated AtROP6 that accumulated in detergent-resistant membranes was modified by prenyl and acyl lipids. The acyl lipids were identified as palmitic and stearic acids. In agreement, activated His(6)-GFP-Atrop6(CA)mS(156) in which cysteine(156) was mutated into serine accumulated in Triton-soluble membranes. These findings show that upon GTP binding and activation, AtROP6 and possibly other ROPs are transiently S acylated, which induces their partitioning into detergent-resistant membranes.
Mol Cell Biol 2007 03
PMID:Activation status-coupled transient S acylation determines membrane partitioning of a plant Rho-related GTPase. 2889 27


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