Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033774 (pruritus)
 14,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nasal histamine (H), leukotriene C4 (I-LTC4) and SRS-A activity were studied in seven aspirin-(ASA)-intolerant patients (AIR) with rhinitis and in five ASA-tolerant control patients with chronic rhinitis after nasal provocation (NP) with a lysine acetylsalicylate solution. The same parameters were also studied after metabisulfite (MBS) NP in four sulfite-intolerant patients with rhinitis and in six control patients with chronic rhinitis. In six ASA-intolerant subjects and in four controls, we studied the PGD2 levels in nasal washes after ASA NP 0.2 mL of lysine acetylsalicylate solution (10 mg/mL) was sprayed intranasally in ASA-intolerant patients and controls and a 25-mg/mL MBS solution in sulfite intolerant patients and controls. Nasal wash fluids were obtained using 5 mL of 0.15 M saline before and 7 1/2, 15, 30, and 60 minutes after nasal provocation. The nasal provocation with ASA induced itching and sneezing in four out of seven intolerant subjects. In this subgroup histamine values in nasal wash fluids were significantly higher versus the remaining ASA-intolerant patients at 30 and 60 minutes (P less than .05 and P less than .01, respectively) and versus controls at 60 minutes (P less than .01). We found significantly higher I-LTC4 (P less than .01) and SRS-A levels in nasal washes collected from ASA-intolerant subjects versus controls at 60 minutes after nasal provocation. There was no significant increase in the mean PGD2 values in either the ASA-intolerant or control groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Study of mediators of anaphylaxis in nasal wash fluids after aspirin and sodium metabisulfite nasal provocation in intolerant rhinitic patients. 368 66

A novel mode of crosstalk between the EGFR-Ras-MAPK and LIN-12/Notch pathways occurs during the patterning of a row of vulval precursor cells (VPCs) in Caenorhabditis elegans: activation of the EGFR-Ras-MAPK pathway in the central VPC promotes endocytosis and degradation of LIN-12 protein. LIN-12 downregulation in the central VPC is a prerequisite for the activity of the lateral signal, which activates LIN-12 in neighboring VPCs. Here we characterize cis-acting targeting sequences in the LIN-12 intracellular domain and find that in addition to a di-leucine motif, serine/threonine residues are important for internalization and lysine residues are important for post-internalization trafficking and degradation. We also identify two trans-acting factors that are required for post-internalization trafficking and degradation: ALX-1, a homolog of yeast Bro1p and mammalian Alix and the WWP-1/Su(dx)/Itch ubiquitin ligase. By examining the effects of mutated forms of LIN-12 and reduced wwp-1 or alx-1 activity on subcellular localization and activity of LIN-12, we provide evidence that the lateral signal-inhibiting activity of LIN-12 resides in the extracellular domain and occurs at the apical surface of the VPCs.
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PMID:LIN-12/Notch trafficking and regulation of DSL ligand activity during vulval induction in Caenorhabditis elegans. 1623 69

Nonallergic rhinitis with eosinophilia is characterized by persistent nasal symptoms without allergy and by a marked eosinophil recruitment in the nasal cavities. The incidence of it is more than 15% among all types of rhinitis. A part of them is caused by nonsteroidal anti-inflammatory drugs hypersensivity. For this study 114 patients were selected on the basis of perennial rhinitis, the absence of allergy and with an eosinophil count higher than 10% of total leukocytes in nasal cytology. In all of them the nasal provocation test with lysine-aspirin was made. The clinical response was evaluated based on nasal symptoms (sneezes, itching, secretion and blockage). The nasal response was measured by acoustic rhinometry. The results of the test was positive in 19 cases, mostly in patients with nasal polyps, bronchial asthma and higher level of nasal eosinophilia (differences statistically significant). The count of nasal eosinophilia corresponded better with the decrease of nasal volume in acoustic rhinometry (r = 0,84) then with the clinical score (r = 0,52). The nasal challenge was well tolerated by almost all subjects. We conclude that the nasal challenge with lysine-aspirin is safe and can be helpful as a diagnostic test in patients with nonallergic rhinitis with eosinophilia.
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PMID:[Nasal provocation test with lysine-aspirin in diagnosis of nonallergic rhinitis with eosinophilia]. 1682 37

p63, a protein related to the tumor suppressor p53, is a transcription factor that plays an important role in epidermal differentiation and limb development. The gene has two distinct promoters that allow the formation of proteins that either contain (TA) or lack (DeltaN) a transactivation domain. In addition, alternative splicing at the 3' end generates proteins with different C-termini, denoted alpha, beta and gamma for a total of six isoforms. DeltaNp63alpha isoform is the main isoform expressed at all stages of development, however the relative contribution of individual p63 isoform during ectodermal differentiation and organogenesis is still far from understood. Overexpression of DeltaNp63 led to increased growth of transformed cells in vitro and in vivo while treatment of keratinocytes with ultraviolet irradiation causes downregulation of DeltaNp63 proteins and their corresponding mRNA. The p63 gene locus is often amplified in squamous cell carcinomas while alterations in the relative levels of TA and DeltaNp63 correlate with prognosis in several human cancers suggesting that fine regulation of p63 intracellular levels must be of pivotal importance in controlling cell proliferation, death and differentiation. Despite its relevance little is known on the mechanisms controlling p63 protein levels. Here we show that Itch/AIP4, a HECT E3-ubiquitin ligase, promotes p63 degradation. Using a set of p63 deletion mutants, we have identified a region and two critical lysine residues of p63, associated to human Split-Hand and Foot Malformation-4 (SHFM-4) syndrome, which are involved in the mechanism of Itch-mediated p63 degradation.
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PMID:Itch/AIP4 associates with and promotes p63 protein degradation. 1693 10

We have developed a system for producing biotinylated recombinant proteins in mammalian cells. The expression construct consists of an inducible tetracycline response element (TRE) that drives expression of a bicistronic cassette comprising a biotin acceptor peptide (BioTag) fused to either terminus of the target protein, the gene for Escherichia coli biotin ligase (BirA), and an intervening internal ribosome entry site (IRES). By either transient or stable transfection of Chinese hamster ovary (CHO) Tet-On cells, we successfully expressed, detected, and immobilized biotinylated human Itch, a pleiotropic multi-domain ubiquitin-protein ligase, as well as Gla-RTK, a putative vitamin K-dependent receptor tyrosine kinase. The biotinylation of recombinant Itch in transiently transfected CHO Tet-On cells required biotin supplementation and coexpression of BirA, occurred quantitatively and specifically on the lysine residue of the BioTag, and enabled detection of Itch by Western blot in as little as 10ng of total lysate protein. Stably selected clones were rapidly pre-screened for doxycycline (dox)-inducible BirA expression by ELISA, and subsequently screened for dox-inducible expression of biotinylated Itch. Biotinylated Gla-RTK was detectable in as little as 5ng of total lysate protein from transiently transfected CHO Tet-On cells, and exhibited pronounced tyrosine phosphorylation. In stable clones however, constitutive phosphorylation was prevented by reducing the expression level of Gla-RTK through the titration of dox. These results demonstrate the utility of this system for the expression of 'difficult' proteins, particularly those that are cytotoxic or those that may require lower expression levels to ensure appropriate post-translational modification.
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PMID:A versatile system for site-specific enzymatic biotinylation and regulated expression of proteins in cultured mammalian cells. 1708 93

Polyubiquitination can mediate several different biochemical functions, determined in part by which lysine of ubiquitin is used to link the polyubiquitin chain. Among the HECT domain ubiquitin ligases, some, such as human E6AP, preferentially catalyze the formation of K48-linked polyubiquitin chains, while others, including Saccharomyces cerevisiae Rsp5 and human Itch, preferentially catalyze the formation of K63-linked chains. The features of HECT E3s that determine their chain type specificities have not been identified. We show here that chain type specificity is a function solely of the Rsp5 HECT domain, that the identity of the cooperating E2 protein does not influence the chain type specificity, that single chains produced by Rsp5 contain between 12 and 30 ubiquitin moieties, and that the determinants of chain type specificity are located within the last 60 amino acids of the C lobe of the HECT domain. Our results are also consistent with a simple sequential-addition mechanism for polyubiquitination by Rsp5, rather than a mechanism involving the formation of either E2- or E3-linked polyubiquitin chain transfers.
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PMID:Polyubiquitination by HECT E3s and the determinants of chain type specificity. 1936 24

Chemical modifications of nociceptin/orphanin FQ (N/OFQ) peptide that result in increased potency and resistance to degradation have recently lead to the discovery of [(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2) (UFP-112), a novel N/OFQ peptide (NOP) receptor agonist. The aim of this study was to investigate the pharmacological profile of intrathecally administered UFP-112 in monkeys under different behavioral assays. Intrathecal UFP-112 (1-10 nmol) dose-dependently produced antinociception against an acute noxious stimulus (50 degrees C water) and capsaicin-induced thermal hyperalgesia. Intrathecal UFP-112-induced antinociception could be reversed by a NOP receptor antagonist, J-113397 (0.1mg/kg), but not by a classic opioid receptor antagonist, naltrexone (0.03 mg/kg). Like intrathecal morphine, UFP-112 produced antinociception in two primate pain models with a similar magnitude of effectiveness and a similar duration of action that last for 4-5h. Unlike intrathecal morphine, UFP-112 did not produce itch/scratching responses. In addition, intrathecal inactive doses of UFP-112 and morphine produced significant antinociceptive effects when given in combination without increasing scratching responses. These results demonstrated that intrathecal UFP-112 produced long-lasting morphine-comparable antinociceptive effects without potential itch side effect. This study is the first to provide functional evidence that selective NOP receptor agonists such as UFP-112 alone or in conjunction with morphine may improve the quality of spinal analgesia.
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PMID:Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112. 1994 94

The homeodomain protein TGIF functions as a negative regulator of multiple classes of transcription factors. Here we report on the characterization of TGIF as an essential component of the tumor necrosis factor alpha (TNF-alpha) cytotoxic program. This proapoptotic role of TGIF does not appear to rely on transcriptional modulation but instead is executed in conjunction with Itch/AIP4, an E3 ubiquitin ligase operating in TNF-alpha-induced apoptosis through its ability to target the caspase antagonist cFlip(L) for degradation. Notably, we found that activation of TNF-alpha signaling induced the association of TGIF with Itch/AIP4, resulting in increased accessibility of cFlip(L) for association and ubiquitination by Itch/AIP4. Moreover, we show that Itch/AIP4 can also stabilize the TGIF protein in response to TNF-alpha by triggering its monoubiquitination at lysine 259, thereby revealing the existence of a functional network that can evolve into a positive feedback loop for ensuring effective execution of the TNF-alpha apoptotic signaling.
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PMID:A model of partnership co-opted by the homeodomain protein TGIF and the Itch/AIP4 ubiquitin ligase for effective execution of TNF-alpha cytotoxicity. 2006 71

Bone morphogenetic proteins (BMPs) are critically involved in early development and cell differentiation. In humans, dysfunction of the bone morphogenetic protein type II receptor (BMPR-II) is associated with pulmonary arterial hypertension (PAH) and neoplasia. The ability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma and primary effusion lymphoma, to down-regulate cell surface receptor expression is well documented. Here we show that KSHV infection reduces cell surface BMPR-II. We propose that this occurs through the expression of the viral lytic gene, K5, a ubiquitin E3 ligase. Ectopic expression of K5 leads to BMPR-II ubiquitination and lysosomal degradation with a consequent decrease in BMP signaling. The down-regulation by K5 is dependent on both its RING domain and a membrane-proximal lysine in the cytoplasmic domain of BMPR-II. We demonstrate that expression of BMPR-II protein is constitutively regulated by lysosomal degradation in vascular cells and provide preliminary evidence for the involvement of the mammalian E3 ligase, Itch, in the constitutive degradation of BMPR-II. Disruption of BMP signaling may therefore play a role in the pathobiology of diseases caused by KSHV infection, as well as KSHV-associated tumorigenesis and vascular disease.
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PMID:Identification of a lysosomal pathway regulating degradation of the bone morphogenetic protein receptor type II. 2087 Jul 17

The adaptor protein Amot130 scaffolds components of the Hippo pathway to promote the inhibition of cell growth. This study describes how Amot130 through binding and activating the ubiquitin ligase AIP4/Itch achieves these effects. AIP4 is found to bind and ubiquitinate Amot130 at residue Lys-481. This both stabilizes Amot130 and promotes its residence at the plasma membrane. Furthermore, Amot130 is shown to scaffold a complex containing overexpressed AIP4 and the transcriptional co-activator Yes-associated protein (YAP). Consequently, Amot130 promotes the ubiquitination of YAP by AIP4 and prevents AIP4 from binding to large tumor suppressor 1. Amot130 is found to reduce YAP stability. Importantly, Amot130 inhibition of YAP dependent transcription is reversed by AIP4 silencing, whereas Amot130 and AIP4 expression interdependently suppress cell growth. Thus, Amot130 repurposes AIP4 from its previously described role in degrading large tumor suppressor 1 to the inhibition of YAP and cell growth.
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PMID:Amot130 adapts atrophin-1 interacting protein 4 to inhibit yes-associated protein signaling and cell growth. 2356 55


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