Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.27.1 (RNase)
 16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effector cell protease receptor-1 (EPR-1) is a transmembrane glycoprotein receptor for factor Xa that contributes to cell surface assembly of proteolytic activities and leukocyte mitogenesis. It is now shown that membrane expression of EPR-1 is dynamically modulated by mRNA splicing. Northern hybridization analysis of EPR-1-expressing cells and genetically engineered transfectants demonstrates that this mechanism involves removal of a 451 bp intervening sequence retained in 70-90% of mature mRNA, as quantitated by polymerase chain reaction amplification and ribonuclease protection studies. Splicing of the intervening sequence occurs in a cell type-specific fashion, as judged by the constitutive membrane overexpression of EPR-1 in certain leukemic B lymphocytes and monocytic cells. Furthermore, phenotypic analysis of cell lines stably transfected with functionally spliced or unspliced EPR-1 constructs suggests a potential role of intron cis-acting sequence(s) in splicing regulation. Instead of a transmembrane receptor for factor Xa (EPR-1a), the most prevalent unspliced EPR-1 transcript generates a novel truncated protein of 110 amino acids (EPR-1b), in which a unique intron-encoded -COOH terminus carries a potential nuclear targeting signal PPQHRAKS. An antibody generated against the intron-encoded sequence of EPR-1b demonstrates prominent nuclear localization of this variant isoform in indirect immunofluorescence staining of permeabilized cells. These findings provide evidence for a novel mechanism based on high efficiency intron retention modulating factor Xa-dependent cellular effector functions.
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PMID:Splicing of effector cell protease receptor-1 mRNA is modulated by an unusual retained intron. 794 93

A major response of eukaryotic cells to the presence of unfolded proteins in the lumen of the endoplasmic reticulum (ER) is to activate genes that encode ER-located molecular chaperones, such as the binding protein. This response, called the unfolded protein response, requires the transduction of a signal from the ER to the nucleus. In yeast (Saccharomyces cerevisiae) and mammalian cells, an ER-located transmembrane receptor protein kinase/ribonuclease called Ire1, with a sensor domain in the lumen of the ER, is the first component of this pathway. Here, we report the cloning and derived amino acid sequences of AtIre1-1 and AtIre1-2, two Arabidopsis homologs of Ire1. The two proteins are located in the perinuclear ER (based on heterologous expression of fusions with green fluorescent protein). The expression patterns of the two genes (using beta-glucuronidase fusions) are nearly nonoverlapping. We also demonstrate functional complementation of the sensor domains of the two proteins in yeast and show that the Ire1-2 protein is capable of autotransphosphorylation. These and other findings are discussed in relation to the involvement of these genes in unfolded protein response signaling in plants.
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PMID:Molecular characterization of two Arabidopsis Ire1 homologs, endoplasmic reticulum-located transmembrane protein kinases. 1170 77

Self-incompatibility (SI) prevents the production of "self" seed and inbreeding by providing a recognition and rejection system for "self," or genetically identical, pollen. Studies of gametophytic SI (GSI) species at a molecular level have identified two completely different S-genes and SI mechanisms. One GSI mechanism, which is found in the Solanaceae, Rosaceae and Scrophulariaceae, has S-RNase as the pistil S-component and an F-box protein as the pollen S-component. However, non-S-locus factors are also required. In an incompatible situation, the S-RNases degrade pollen RNA, thereby preventing pollen tube growth. Here, in the light of recent evidence, we examine alternative models for how compatible pollen escapes this cytotoxic activity. The other GSI mechanism, so far found only in the Papaveraceae, has a small secreted peptide, the S-protein, as its pistil S-component. The pollen S-component remains elusive, but it is thought to be a transmembrane receptor, as interaction of the S-protein with incompatible pollen triggers a signaling network, resulting in rapid actin depolymerization and pollen tube inhibition and programmed cell death (PCD). Here, we present an overview of what is currently known about the mechanisms involved in regulating pollen tube inhibition in these two GSI systems.
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PMID:Gametophytic self-incompatibility: understanding the cellular mechanisms involved in "self" pollen tube inhibition. 1679 41

Activation of the ER stress response is associated with malignant progression of B cell chronic lymphocytic leukemia (CLL). We developed a murine CLL model that lacks the ER stress-associated transcription factor XBP-1 in B cells and found that XBP-1 deficiency decelerates malignant progression of CLL-associated disease. XBP-1 deficiency resulted in acquisition of phenotypes that are disadvantageous for leukemic cell survival, including compromised BCR signaling capability and increased surface expression of sphingosine-1-phosphate receptor 1 (S1P1). Because XBP-1 expression requires the RNase activity of the ER transmembrane receptor IRE-1, we developed a potent IRE-1 RNase inhibitor through chemical synthesis and modified the structure to facilitate entry into cells to target the IRE-1/XBP-1 pathway. Treatment of CLL cells with this inhibitor (B-I09) mimicked XBP-1 deficiency, including upregulation of IRE-1 expression and compromised BCR signaling. Moreover, B-I09 treatment did not affect the transport of secretory and integral membrane-bound proteins. Administration of B-I09 to CLL tumor-bearing mice suppressed leukemic progression by inducing apoptosis and did not cause systemic toxicity. Additionally, B-I09 and ibrutinib, an FDA-approved BTK inhibitor, synergized to induce apoptosis in B cell leukemia, lymphoma, and multiple myeloma. These data indicate that targeting XBP-1 has potential as a treatment strategy, not only for multiple myeloma, but also for mature B cell leukemia and lymphoma.
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PMID:Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival. 2481 69

We studied the localization of transmembrane receptor P185(HER2) in SKOV-3 and BT-474 cancer cells by fluorescence, confocal and electron immunomicroscopy. P185(HER2) is a marker of breast and ovarian tumors, it is considered as a target for anticancer therapy. It is extremely important to choose a universal immunicytotoxic agent applicable, first, to study the distribution of P185(HER2) in cancer cells, secondly, to remove P185(HER2) from the cell surface and, thirdly, to eliminate target cells. In this work for visualization of P185HER2 We prOposed immunocytotoxic system, consisting of the monoclonal miniantibody 4D5 scFv to extracellular P185E domain fused with two molecules of barnase (ribonuclease from Bacillus amyloliquefaciens) and of its specific inhibitor barstar. Fluorescence microscopy has showed that the module 4D5 scFv-dibarnase:barstar efficiently identified P185(HER2) on the surface of cancer cells. It was revealed by confocal microscopy that interaction with 4D5 scFv-dibarnase lead to internalization of P185(HER2). The localization of P185(HER) in human ovarian carcinoma cells SKOV-3 and breast carcinoma cells BT-474 was compared by electron microscopy using 4D5 scFv-dibarnase:barstar-Au and 4D5 scFv-dibarnase-Au complexes. P185(HER) distributed on the cell surface unequally with preferential localization on protrusions or close to their bases and in contacts between protrusions and cell membrane. At 37 degrees C, P185(HER2) internalized through coated pits and vesicles and concentrated in the endosomes and multivesicular bodies in the cells of both cell lines, as well as in lysosomes in cells BT-474.
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PMID:[Immunocytochemical visualization of P185(HER2) receptor by antibody fused with dibarnase and conjugate of barstar with colloidal gold]. 2550 53