Caroline M. Milner
University of Oxford
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Featured researches published by Caroline M. Milner.
Immunogenetics | 1990
Caroline M. Milner; R. Duncan Campbell
A duplicated locus encoding the major heat shock-induced protein HSP70 is located in the major histocompatibility complex (MHC) class III region 92 kilobases (kb) telomeric to the C2 gene. Nucleotide sequence analysis of the two intronless genes, HSP70-1 and HSP70-2, has shown that they encode an identical protein product of 641 amino acids. A third intronless gene, HSP70-Hom, has also been identified 4 kb telomeric to the HSP70-1 gene. This encodes a more basic protein of 641 amino acids which has 90% sequence similarity with HSP70-1. In order to investigate the expression of the three (MHC)-linked HSP70 genes individually by northern blot analysis, we have isolated locus-specific probes from the 3′ untranslated regions of the genes. The HSP70-1 and HSP70-2 genes have been shown to be expressed at high levels as a ∼ 2.4 kb mRNA in cells heat-shocked at 42°C. HSP70-1 is also expressed constitutively at very low levels. The HSP70-Hom gene, which has no heat shock consensus sequence in its 5′ flanking sequence, is expressed as a ∼3 kb mRNA at low levels both constitutively and following heat shock.
Biochemical Society Transactions | 2006
Caroline M. Milner; Victoria A. Higman; Anthony J. Day
TSG-6 is a multifunctional protein that is up-regulated in many pathological and physiological contexts, where it plays important roles in inflammation and tissue remodelling. For example, it is a potent inhibitor of neutrophil migration and can modulate the protease network through inhibition of plasmin. TSG-6 binds a wide range of GAGs (glycosaminoglycans) [i.e. HA (hyaluronan), chondroitin 4-sulphate, dermatan sulphate, heparin and heparan sulphate] as well as a variety of protein ligands, where these interactions can influence the activities of TSG-6. For example, through its association with HA, TSG-6 can mediate HA cross-linking via several different mechanisms, some of which promote leucocyte adhesion. Binding to heparin, however, enhances the ability of TSG-6 to potentiate the anti-plasmin activity of inter-alpha-inhibitor, which binds non-covalently to TSG-6 via its bikunin chain. Furthermore, although HA and heparin interact with distinct sites on the Link module, the binding of heparin can inhibit subsequent interaction with HA. In addition, the interactions of TSG-6 with HA, heparin and at least some of its protein ligands are sensitive to pH. Therefore it seems that in different tissue micro-environments (characterized, for example, by pH and GAG content), TSG-6 could be partitioned into functional pools with distinct activities.
Immunogenetics | 1992
Caroline M. Milner; R. Duncan Campbell
Three genes encoding members of the Mr 70 000 heat shock protein family (HSP70) are known to lie in the class III region of the human major histocompatibility complex. IN order to determine whether these genes or their protein products exhibit any polymorphism the three genes have been specifically amplified from genomic DNA and sequenced. The HSP70-1 and HSP70-2 genes encode the major heat-inducible HSP70. A comparison of the nucleotide sequences of these genes from B8, SC01, DR3, B18, F1C30, DR3, and B7, SC30, DR2 haplotypes has revelad only very limited sequence variation which is not associated with any amino acid polymorphism. The HSP70-Hom gene encodes a protein that is highly related to HSP70-1, but which is not heat-inducible. Nucleotide sequence analysis of this gene from different haplotypes has revealed a Met → Thr amino acid substitution at residue 493 in a number of the haplotypes tested. This variable amino acid lies in the proposed peptide-binding site of the HSP70-Hom protein.
Journal of Biological Chemistry | 1997
Caroline M. Milner; Smith Sv; Carrillo Mb; Taylor Gl; Michael Hollinshead; Campbell Rd
Mammalian sialidases are important in modulating the sialic acid content of cell-surface and intracellular glycoproteins. However, the full extent of this enzyme family and the physical and biochemical properties of its individual members are unclear. We have identified a novel gene, G9, in the human major histocompatibility complex (MHC), that encodes a 415-amino acid protein sharing 21-28% sequence identity with the bacterial sialidases and containing three copies of the Asp-block motif characteristic of these enzymes. The level of sequence identity between human G9 and a cytosolic sialidase identified in rat and hamster (28-29%) is much less than would be expected for analogous proteins in these species, suggesting that G9 is distinct from the cytosolic enzyme. Expression of G9 in insect cells has confirmed that it encodes a sialidase, which shows optimal activity at pH 4.6, but appears to have limited substrate specificity. The G9 protein carries an N-terminal signal sequence and immunofluorescence staining of COS7 cells expressing recombinant G9 shows localization of this sialidase exclusively to the endoplasmic reticulum. The location of the G9 gene, within the human MHC, corresponds to that of the murine Neu-1 locus, suggesting that these are analogous genes. One of the functions attributed to Neu-1 is the up-regulation of sialidase activity during T cell activation.
International Journal of Cancer | 2001
Takehito Kato; Yan Wang; Kazunori Yamaguchi; Caroline M. Milner; Ryuzaburo Shineha; Susumu Satomi; Taeko Miyagi
Increased sialylation in cell surface glycoproteins is one characteristic feature of cancer cells, particularly related to their metastatic potential and invasiveness. Expression of lysosomal‐type sialidase, which plays a major role in hydrolysis of such sialo‐glycoproteins, is therefore considered to have a great influence on malignant properties of cancer cells. To investigate whether the sialidase expression level is linked to the malignant phenotype, we transfected B16‐BL6 murine melanoma cells, a highly invasive and metastatic line, with an expression vector harboring a rat lysosomal sialidase cDNA; then clones were isolated and examined for changes in biological character. Sialidase‐overexpressing cells showed suppression of experimental pulmonary metastasis and tumor progression. The transfectants exhibited diminished cell growth, anchorage‐independent growth and increased sensitivity to apoptosis induced by suspension culture or serum depletion in vitro, but no significant alterations in invasiveness, cell motility and cell attachment to fibronectin, collagen IV and laminin. Flow cytometric analysis with either peanut agglutinin (PNA) or Ricinus communis agglutinin (RCA) lectin revealed that desialylated forms of glycoproteins on the cell surfaces were increased. In particular, a desialylated form of a cell surface glycoprotein of 83 kDa was prominent in the transfectants, as determined by galactose oxidase labeling. These observations indicate that sialidase expression is inversely associated with metastatic potential and tumor growth in cancer cells, probably through a regulation mechanism that suppresses cell growth and anchorage‐independent growth and promotes apoptosis with deprivation of cell anchorage.
Immunogenetics | 1994
Margriet Snoek; Mark G. Olavesen; Huub van Vugt; Caroline M. Milner; Cory Teuscher; R. Duncan Campbell
Experimental allergic orchitis (EAO) is an autoimmune disease of the testis that is controlled by multple genes. The use of recombinant mouse strains has defined the map position of the H-2-associated locus controlling disease susceptibility, Orch-1, within the H-2S/H-2D interval. Over the last few years the definition of the structural organization of the C4-H-2D segment and identification of the recombination sites of the various intra-H-2 recombinations has reduced the map position of Orch-1 to the Hsp70.1-G7 interval. Three Hsp70 genes, Hsp70.1, Hsp70.3, and Hsc70t, and the genes G7b and G7a are located in this segment of DNA. In order to investigate whether Hsc70t is a suitable candidate for Orch-1 we have compared the sequence of the gene from a susceptible and a resistant haplotype.
Archive | 2008
Anthony J. Day; Charles D. Blundell; David J. Mahoney; Marilyn S. Rugg; Caroline M. Milner
Tony Day joined the Immunochemistry Unit in September 1984 to do a 10-month research project on factor H, under the supervision of Bob Sim, for the final year of his chemistry degree at the University of Oxford. He continued working on factor H for his DPhil (1985–1987)– Tony was Bobs second PhD st...
Archive | 2008
R. Duncan Campbell; Caroline M. Milner; Begoña Aguado
The major histocompatibility complex (MHC) is a key region of the human genome that extends over 3.6 Mbp on human chromosome 6p21.3. It was originally identified as containing the genes that encode the Class I and Class II cell surface molecules critical for our immune system to mount responses to a...
Journal of Biological Chemistry | 2005
Marilyn S. Rugg; Antony C. Willis; Durba Mukhopadhyay; Vincent C. Hascall; Erik Fries; Csaba Fülöp; Caroline M. Milner; Anthony J. Day
Journal of Biological Chemistry | 2002
Stephen J. Getting; David J. Mahoney; Thong V. Cao; Marilyn S. Rugg; Erik Fries; Caroline M. Milner; Mauro Perretti; Anthony J. Day