Irene Hunter

University of Aberdeen

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Iain J. McEwan

University of Aberdeen

Graeme F. Nixon

University of Aberdeen

David Skerrow

University of Glasgow

Konrad Beck

Lawrence Livermore National Laboratory

Therese Schulthess

University of Basel

Craig Jamieson

University of Strathclyde

Fiona A. Mathieson

University of Aberdeen

BÖ

Björn Öbrink

Karolinska Institutet

Jürgen Engel

University of Basel

C. R. M. Hay

Memorial Hermann Institute for Rehabilitation and Research Foundation

Cooperative Institutions

University of Aberdeen

Institute for Research in Biomedicine

Institute of Medical Sciences

Institute for Research in Biomedicine

University of Edinburgh

Tongji University

Shanghai Jiao Tong University

University of Glasgow

University of Strathclyde

Universitat Politècnica de Catalunya

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Caspase-Dependent Cleavage of Cadherins and Catenins During Osteoblast Apoptosis

Journal of Bone and Mineral Research (2001)

Irene Hunter D.F.M. McGregor Simon P. Robins

Abstract As transmembrane, Ca2+-dependent cell-cell adhesion molecules, cadherins play a central role in tissue morphogenesis and homeostasis. Stable adhesion is dependent on interactions of the cytoplasmic domain of the cadherins with a group of intracellular proteins, the catenins. In the present study, we have detected the expression of α-, β-, and γ-catenins in human osteoblasts, which assemble with cadherins to form two distinct complexes containing cadherin and α-catenin, with either β- or γ-catenin. In osteoblasts undergoing apoptosis, proteolytic cleavage of N-cadherin and β- and γ- catenins but not α-catenin was associated with the activation of caspase-3 and prevented by the caspase inhibitor Z-VAD-fmk. The pattern of cadherin/catenin cleavage detected in apoptotic osteoblasts was reproduced in vitro by recombinant caspase-3. The presence of a 90-kDa extracellular domain fragment of N-cadherin in conditioned medium from apoptotic cells indicates that additional extracellular or membrane-associated proteases also are activated. Disruption of N-cadherin-mediated cell-cell adhesion with function-blocking antibodies induced osteoblast apoptosis, activation of caspases, and cleavage of β-catenin. These findings provide compelling evidence that N-cadherin-mediated cell-cell adhesion promotes osteoblast survival and suggest that the underlying mechanism may involve activation of β-catenin signaling.

Cleavage (geology)

Beta-catenin

10.1359/jbmr.2001.16.3.466

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Citations (35)

Stimulation of stress-activated but not mitogen-activated protein kinases by tumour necrosis factor receptor subtypes in airway smooth muscle

Biochemical Pharmacology (2001)

Shona M. McFarlane Orla J. Jupp Hannah J. Cobban Irene Hunter Helen M. Anderson

10.1016/s0006-2952(01)00530-5

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Citations (26)

Current and emerging approaches to noncompetitive AR inhibition

Medicinal Research Reviews (2023)

Christopher M. Riley J Mark Elwood Martyn C. Henry Irene Hunter J. Daniel Lopez‐Fernandez

Abstract The androgen receptor (AR) has been shown to be a key determinant in the pathogenesis of castration‐resistant prostate cancer (CRPC). The current standard of care therapies targets the ligand‐binding domain of the receptor and can afford improvements to life expectancy often only in the order of months before resistance occurs. Emerging preclinical and clinical compounds that inhibit receptor activity via differentiated mechanisms of action which are orthogonal to current antiandrogens show promise for overcoming treatment resistance. In this review, we present an authoritative summary of molecules that noncompetitively target the AR. Emerging small molecule strategies for targeting alternative domains of the AR represent a promising area of research that shows significant potential for future therapies. The overall quality of lead candidates in the area of noncompetitive AR inhibition is discussed, and it identifies the key chemotypes and associated properties which are likely to be, or are currently, positioned to be first in human applications.

Antiandrogens

10.1002/med.21961

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Citations (7)

Control of cortex development by ULK4, a rare risk gene for mental disorders including schizophrenia

Scientific Reports (2016)

Bing Lang Lei Zhang Guanyu Jiang Ling Hu Wei Lan

Schizophrenia is a debilitating familial neuropsychiatric disorder which affects 1% of people worldwide. Although the heritability for schizophrenia approaches 80% only a small proportion of the overall genetic risk has been accounted for, and to date only a limited number of genetic loci have been definitively implicated. We have identified recently through genetic and in vitro functional studies, a novel serine/threonine kinase gene, unc-51-like kinase 4 (ULK4), as a rare risk factor for major mental disorders including schizophrenia. Now using the approach of in utero gene transfer we have discovered that Ulk4 plays a key modulatory role in corticogenesis. Knockdown of Ulk4 leads to significantly decreased cell proliferation in germinal zones and profound deficits in radial migration and neurite ramification. These abnormalities can be reversed successfully by Ulk4 gene supplementation. Ulk4 also regulated acetylation of α-tubulin, an important post-translational modification of microtubules. We conclude that Ulk4 plays an essential role in normal brain development and when defective, the risk of neurodevelopmental disorders such as schizophrenia is increased.

10.1038/srep31126

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Citations (35)

Macrophage-Inflammatory Protein-1α Regulates Preosteoclast Differentiationin Vitro

Biochemical and Biophysical Research Communications (1999)

Ben A. Scheven John S. Milne Irene Hunter Simon P. Robins

Macrophage inflammatory protein

Polyclonal antibodies

10.1006/bbrc.1998.9909

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Citations (73)

Dissection of the bovine epidermal desmosome into cytoplasmic protein and membrane glycoprotein domains

Journal of Cell Science (1987)

Christine J. Skerrow Irene Hunter David Skerrow

ABSTRACT Epidermal desmosomes contain two main regions. The core consists of a pair of membranes, one on either side of a cross-striated intercellular space bisected by a denser midline. The cytoplasmic compartment comprises a dense plaque deposited on the cytoplasmic surface of each membrane and a diffuse layer occupying the zone between the plaque and attached cr-keratin filaments. Analysis of isolated desmosomes by SDS-PAGE has shown the presence of four major protein (dpl-4) and three major glycoprotein (dgl-3) bands, which have been allocated to the cytoplasmic and core compartments, respectively. In the present paper, we report the use of urea to fractionate this complex structure, both in situ and following isolation with citrate buffer, pH2’6. Extraction of the living layers of bovine epidermis with 9M-urea, pH 7 · 5, resulted in rapid removal of the dense desmosomal plaques, followed by separation and vésiculation of desmosomal membranes. The resistance of the plaque to urea increased abruptly at the transition between living epidermis and dead, dehydrated horny layer. A similar sequence of morphological changes accompanied the extraction of isolated desmosomes with urea. Analysis of residues and extracts of isolated desmosomes by SDS-PAGE confirmed the selectivity of 9M-urea, pH 7 · 5, for the cytoplasmic compartment. The four major desmosomal proteins, dpl-4 (Mr240, 215, 90 and 83 (× 103), respectively) predominated in the extracts. Desmosomal membranes, both paired and vesiculated, consisted almost entirely of the three desmosomal glycoproteins dgl-3 (Mr 150, 120 and 110 (× 103), respectively). These results provide evidence that all three desmosomal glycoproteins are integral membrane proteins. The separation of desmosomal membranes by urea, which is not accompanied by additional loss of proteins, further suggests that desmosomal adhesion is based on interactions between membrane components with no separate extracellular molecules being involved. The dissection of the desmosome by urea into two topographically and biochemically distinct domains should facilitate further studies on the molecular basis of desmosomal adhesion and a- keratin filament binding.

Desmosome

Epidermis (zoology)

10.1242/jcs.87.3.411

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Citations (14)

The cell adhesion molecule C‐CAM is a substrate for tissue transglutaminase

FEBS Letters (1998)

Irene Hunter Kristmundur Sigmundsson Nicole Beauchemin Björn Öbrink

C‐CAM, a ubiquitously expressed cell adhesion molecule belonging to the carcinoembryonic antigen family, appears as two co‐expressed isoforms, C‐CAM‐L and C‐CAM‐S, with different cytoplasmic domains, that can form homo‐dimers in epithelial cells. In addition, C‐CAM‐L has been found in large molecular weight forms suggesting posttranslational, covalent modification. Here we have investigated the possibility that the cytoplasmic domain of C‐CAM‐L can act as a transglutaminase substrate. Glutathione S ‐transferase fusion proteins of the cytoplasmic domains of rat and mouse C‐CAM‐L as well as free cytoplasmic domains, released by thrombin cleavage from the fusion proteins, were converted into covalent dimers by tissue transglutaminase. These results demonstrate that the cytoplasmic domains of rat and mouse C‐CAM‐L are substrates for tissue transglutaminase, and lend support to the notion that higher molecular weight forms of C‐CAM‐L are formed by transglutaminase modification.

Tissue transglutaminase

10.1016/s0014-5793(98)00223-3

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Citations (14)

Assembly of laminin isoforms by triple- and double-stranded coiled-coil structures

Biochemical Society Transactions (1991)

Jürgen Engel Irene Hunter Therese Schulthess Konrad Beck Tony W. Dixon

Conference Article| November 01 1991 Assembly of laminin isoforms by triple- and double-stranded coiled-coil structures Jürgen Engel; Jürgen Engel *Department of Biophysical Chemistry, Biozentrum of the University of Basel, CH-4056 Basel, Switzerland Search for other works by this author on: This Site PubMed Google Scholar Irene Hunter; Irene Hunter *Department of Biophysical Chemistry, Biozentrum of the University of Basel, CH-4056 Basel, Switzerland Search for other works by this author on: This Site PubMed Google Scholar Therese Schulthess; Therese Schulthess *Department of Biophysical Chemistry, Biozentrum of the University of Basel, CH-4056 Basel, Switzerland Search for other works by this author on: This Site PubMed Google Scholar Konrad Beck; Konrad Beck †Institute for Biophysics, University of Linz, A-4040 Linz, Austria Search for other works by this author on: This Site PubMed Google Scholar Tony W. Dixon; Tony W. Dixon ‡Department of Physics and Biophysics, Massey University, Palmerston North, New Zealand Search for other works by this author on: This Site PubMed Google Scholar David A. D. Parry David A. D. Parry ‡Department of Physics and Biophysics, Massey University, Palmerston North, New Zealand Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1991) 19 (4): 839–843. https://doi.org/10.1042/bst0190839 Article history Received: July 25 1991 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation Jürgen Engel, Irene Hunter, Therese Schulthess, Konrad Beck, Tony W. Dixon, David A. D. Parry; Assembly of laminin isoforms by triple- and double-stranded coiled-coil structures. Biochem Soc Trans 1 November 1991; 19 (4): 839–843. doi: https://doi.org/10.1042/bst0190839 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search Keywords: ECM, extracellular matrix, EHS, Engelbreth-Holm-Swarm © 1991 Biochemical Society1991 Article PDF first page preview Close Modal You do not currently have access to this content.

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10.1042/bst0190839

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Citations (35)

Recurrent deletions of ULK4 in schizophrenia: a novel gene crucial for neuritogenesis and neuronal motility

Journal of Cell Science (2013)

Bing Lang Jin Pu Irene Hunter Min Liu Cristina Martín‐Granados

Although many pathogenic copy number variations (CNVs) are associated with neuropsychiatric diseases, few of them have been functionally characterised. Here we report multiple schizophrenia cases with CNV abnormalities specific to unc-51-like kinase 4 (ULK4), a novel serine/threonine kinase gene. Deletions spanning exons 21–34 of ULK4 were present in 4 out of 3,391 schizophrenia patients from the International Schizophrenia Consortium, but absent in 3,181 controls. Deletions removing exons 33 and 34 of the large splice variant of ULK4 also were enriched in Icelandic schizophrenia and bipolar patients compared to 98,022 controls (P=0.0007 for schizophrenia plus bipolar disorder). Combining the two cohorts gives a p value less than 0.0001 for schizophrenia, or for schizophrenia plus bipolar disorder. The expression of ULK4 is neuron-specific and developmentally regulated. ULK4 modulates multiple signalling pathways including ERK, p38, PKC, and JNK, which are involved in stress responses and implicated in schizophrenia. Knockdown of ULK4 disrupts the composition of microtubules and compromises neuritogenesis and cell motility. Targeted Ulk4 deletion causes corpus callosum agenesis in mice. Our findings indicate that ULK4 is a rare susceptibility gene for schizophrenia.

10.1242/jcs.137604

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Citations (76)

A phospholipase C 1-activated pathway regulates transcription in human vascular smooth muscle cells

Cardiovascular Research (2011)

Irene Hunter Keith Mascall Joe W. Ramos Graeme F. Nixon

AimsGrowth factor-induced repression of smooth muscle (SM) cell marker genes is an integral part of vascular SM (VSM) cell proliferation. This is partly regulated via translocation of extracellular signal-regulated kinase 1/2 (ERK1/2) to the nucleus which activates the transcription factor Elk-1. The mediators involved in ERK1/2 nuclear translocation in VSM cells are unknown. The aim of this study is to examine the mechanisms which regulate growth factor-induced nuclear translocation of ERK1/2 and gene expression in VSM cells.

10.1093/cvr/cvr039

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Citations (23)