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A D Cox

Publications and source records attributed to A D Cox.

At least 91 records · Page 5Linked to original sources
PubMed1992

The ras/cholesterol connection: implications for ras oncogenicity.

The frequent detection of mutated ras genes in a variety of cancers (reviewed in Bos, 1988, 1989; Der, 1988) suggests that ras makes a significant contribution to human malignancies (reviewed in Barbacid, 1987; Lacal and Tronick, 1988; Der, 1989). While the role of ras in malignancy is unclear, it is well-established that the association of ras protein with the inner surface of the plasma membrane is critical for triggering ras oncogenicity. The trafficking of ras proteins to the plasma membrane requires a series of three closely linked posttranslational modifications (farnesylation, proteolysis, and carboxymethylation) that are signaled by the consensus C-terminal CAAX motif present on all ras proteins (reviewed in Rine and Kim, 1990; Gibbs, 1991; Der and Cox, 1991). THe recent discovery that an essential intermediate in cholesterol biosynthesis, the isoprenoid farnesol, is attached covalently to ras proteins has stimulated considerable interest and has identified important new directions for studies of ras function. First, understanding the role of farnesol-linked interactions with the plasma membrane may identify the biochemical basis for the oncogenic actions of ras proteins. Second, the enzymes that catalyze the processing steps that trigger membrane association of ras proteins are promising targets for pharmacologic intervention in ras-associated disease. In this review, we summarize our current knowledge of the role of posttranslational processing in ras-membrane interaction and transforming activity. We also provide an update of recent studies addressing the role of isoprenoid modification in the function of ras and of other isoprenoid-modified proteins (reviewed in James and Olson, 1990; Glomset et al., 1990; Maltese, 1990). While this role is likely to be specific for each protein, ras proteins can provide an excellent prototype for understanding the role of isoprenoid modification in protein function.

Amino Acid Sequence↗
PubMed1991

Isoprenoid modification of rab proteins terminating in CC or CXC motifs.

Mevalonate starvation of hamster fibroblasts resulted in a shift of rab1b from the membrane to the cytosolic fraction, suggesting that rab1b depends upon an isoprenoid modification for its membrane localization. rab1b and rab3a proteins expressed in insect cells incorporated a product of [3H]mevalonate, and gas chromatography analysis of material released by Raney nickel cleavage demonstrated that rab1b and rab3a are modified by geranylgeranyl groups. Additionally, in vitro prenylation analysis demonstrated farnesyl modification of H-ras but geranylgeranyl modification of five rab proteins (1a, 1b, 2, 3a, and 6). Together, these results suggest that the carboxyl-terminal CC/CXC motifs (X = any amino acid) specifically signal for addition of geranylgeranyl, but not farnesyl, groups. A rab1b mutant protein lacking the two carboxyl-terminal cysteine residues was not prenylated in vitro. However, since a mutant H-ras protein that terminates with tandem cysteine residues was also not modified, the CC motif may be essential, but not sufficient, to signal prenylation of rab1b. Finally, rab1b and rab3a proteins were not efficient substrates for either farnesyl- or geranylgeranyltransferase activities that modify CAAX-containing proteins (A = any aliphatic amino acid). Therefore, rab proteins may be modified by a prenyltransferase(s) distinct from the prenyltransferases that modify carboxyl-terminal CAAX proteins.

Amino Acid Sequence↗
PubMed1991

Rab1b regulates vesicular transport between the endoplasmic reticulum and successive Golgi compartments.

We report an essential role for the ras-related small GTP-binding protein rab1b in vesicular transport in mammalian cells. mAbs detect rab1b in both the ER and Golgi compartments. Using an assay which reconstitutes transport between the ER and the cis-Golgi compartment, we find that rab1b is required during an initial step in export of protein from the ER. In addition, it is also required for transport of protein between successive cis- and medial-Golgi compartments. We suggest that rab1b may provide a common link between upstream and downstream components of the vesicular fission and fusion machinery functioning in early compartments of the secretory pathway.

Animals↗
PubMed1991

Ionizing groups in lipopolysaccharides of Pseudomonas cepacia in relation to antibiotic resistance.

Contrary to previous reports, lipopolysaccharides from Pseudomonas cepacia contain a 3-deoxyoct-2-ulosonic acid (probably a single residue). The lipopolysaccharides contain only two phosphate residues, one of which apparently forms a phosphodiester bridge between 4-amino-4-deoxyarabinose and a glucosamine residue in lipid A. The second, unlocated phosphate residue occurs mainly as a monoester in some lipopolysaccharides, and mainly as a diester in others. All lipopolysaccharides lack pyrophosphate residues. The results support the view that the resistance of P. cepacia to cationic antibiotics stems from ineffective binding to the outer membrane, as a consequence of the low number of phosphate and carboxylate groups in the lipopolysaccharide, and the presence of the protonated aminodeoxypentose.

Amino Sugars↗
PubMed1991

Evaluation of a home visiting and befriending scheme for young mothers: Newpin.

Befriending schemes to support families with young children are now widespread in the United Kingdom. One such scheme, Newpin, which aims to prevent child abuse is described. Evaluation compared those recruited to befriend as well as those befriended. Assessments at baseline and 6 months' follow-up comprised interviews with mothers, developmental assessments of the children and observation of mother-child interaction using video tapes. All assessments were conducted in the home and similar measures were applied to a control sample in an area where a Newpin scheme was planned. Newpin recruits, whether befrienders or befriended had high rates of adverse early experiences, but depression was more common amongst those referred for befriending. Approximately a third did not sustain involvement in the scheme, but those that did were more likely to have had training as volunteers and mental health problems of more than 2 years' duration.

Child Abuse↗
PubMed1991

Isoprenoid modification and plasma membrane association: critical factors for ras oncogenicity.

Association of ras protein with the plasma membrane is critical for its transforming activity. This association is promoted by a series of post-translational modifications that are signaled by the consensus C-terminal CAAX motif present in all ras proteins. The recent discovery that a 15-carbon isoprenoid (farnesyl) group, derived from an essential intermediate in cholesterol biosynthesis, is attached covalently to ras proteins has stimulated considerable interest and has suggested several important new directions for ras studies. In particular, one promising pharmacologic approach for antagonizing oncogenic ras activity in human malignancies would be to design specific inhibitors of the enzymes that catalyze ras processing and thereby interfere with ras protein association with the plasma membrane.

Amino Acid Sequence↗
PubMed1990

Structure of the putative O antigen containing 2-amino-2-deoxy-L-glucose in the reference strain for Pseudomonas cepacia serogroup O1.

Polymeric material isolated from the lipopolysaccharide of the reference strain of Pseudomonas cepacia serogroup O1 consisted mainly of D-glucose and 2-amino-2-deoxy-L-glucose: rhamnose and O-acetyl groups were also present. As a result of spectroscopic and degradative studies, the disaccharide repeating-unit shown could be assigned to the major polymer present. A possible origin of the minor components is suggested. ----4)-alpha-D-Glcp-(1----3)-alpha-L-GlcpNAc-(1----.

Antigens, Bacterial↗
PubMed1990

Functional analysis of protein N-myristoylation: metabolic labeling studies using three oxygen-substituted analogs of myristic acid and cultured mammalian cells provide evidence for protein-sequence-specific incorporation and analog-specific redistribution.

Covalent attachment of myristic acid (C14:0) to the NH2-terminal glycine residue of a number of cellular, viral, and oncogene-encoded proteins is essential for full expression of their biological function. Substitution of oxygen for methylene groups in this fatty acid does not produce a significant change in chain length or stereochemistry but does result in a reduction in hydrophobicity. These heteroatom-containing analogs serve as alternative substrates for mammalian myristoyl-CoA:protein N-myristoyltransferase (EC 2.3.1.97) and offer the opportunity to explore structure/function relationships of myristate in N-myristoyl proteins. We have synthesized three tritiated analogs of myristate with oxygen substituted for methylene groups at C6, C11, and C13. Metabolic labeling studies were performed with these compounds and (i) a murine myocyte cell line (BC3H1), (ii) a rat fibroblast cell that produces p60v-src (3Xsrc), or (iii) NIH 3T3 cells that have been engineered to express a fusion protein consisting of an 11-residue myristoylation signal from the Rasheed sarcoma virus (RaSV) gag protein linked to c-Ha-ras with a Cys----Ser-186 mutation. This latter mutation prevents isoprenylation and palmitoylation of ras. Two-dimensional gel electrophoresis of membrane and soluble fractions prepared from cell lysates revealed different patterns of incorporation of the analogs into cellular N-myristoyl proteins (i.e., protein-sequence-specific incorporation). In addition, proteins were identified that underwent redistribution from membrane to soluble fractions after incorporating one but not another analog (analog-specific redistribution). Comparable studies using the model RaSV-ras chimeric protein also demonstrated analog-specific differences in incorporation, varying from approximately 25% of the total RaSV-ras chimeric protein with 5-octyloxypentanoate to greater than 50% with 12-methoxydodecanoate. Modification by this latter compound was so extensive that the amount of membrane-associated N-myristoylated protein was decreased. Incorporation of each of the analogs caused a dramatic redistribution to the soluble fraction, comparable to that seen when myristoylation was completely blocked by mutating the protein's site of myristate attachment (glycine) to an alanine residue. The demonstration that these analogs differ in the extent to which they are incorporated and in their ability to cause redistribution of any single protein suggests that they may also have sufficient selectivity to be of potential therapeutic value.

Animals↗
PubMed1989

Structures of the O-specific polymers from the lipopolysaccharides of the reference strains for Pseudomonas cepacia serogroups O3 and O5.

The putative O-specific polymers of lipopolysaccharides from two reference strains of Pseudomonas cepacia have been isolated and characterized. Both polymers have disaccharide repeating-units. Structure 1 was established for the O3 polymer, and structure 2 for the O5 polymer. Polymers with the same repeating units have been found previously as the O antigens of other bacteria. ----2)-beta-D-Ribf-(1----4)-alpha-D-GalpNAc-(1---- ----4)-alpha-L-Rhap-(1----3)-beta-D-ManpNAc-(1----

Amino Sugars↗
PubMed1989

Polar lipids and fatty acids of Pseudomonas cepacia.

The polar lipids and fatty acids produced by the reference strains for seven different O serogroups of Pseudomonas cepacia have been identified. Similar results were obtained for all strains. Contrary to a previous report, the only significant phospholipids in this species are phosphatidylethanolamine and bis(phosphatidyl)glycerol, which contributed 57-83% and 17-43%, respectively, of the total lipid phosphorus. The former lipid was found as two chromatographically distinct fractions. In the less polar fraction and in bis(phosphatidyl)glycerol, the major fatty acids were hexadecanoic acid, cis-9,10-methylenehexadecanoic acid, cis-octadec-11-enoic acid, and cis-11,12-methyleneoctadecanoic acid. In the more polar fraction of phosphatidylethanolamine, the fatty acid in one position is a 2-hydroxy acid, mainly 2-hydroxyhexadecenoic acid, 2-hydroxyhexadecanoic acid, 2-hydroxyoctadecenoic acid, or 2-hydroxymethyleneoctadecanoic acid. Compared with other phospholipids, this fraction of phosphatidylethanolamine was depleted in cis-9,10-methylenehexadecanoic acid. Each strain also produced two ornithine amide lipids. In the major lipid, 3-hydroxyhexadecanoic acid was amide-bound to the alpha-amino group and was itself probably esterified by a 2-hydroxy acid, mainly 2-hydroxyoctadecenoic acid or the derived cyclopropane acid. In the minor ornithine amide lipid, the ester-bound acids were mainly methyleneoctadecanoic acid and hexadecanoic acid. The unusual lipid profiles of P. cepacia are of chemotaxonomic interest.

Chromatography, Thin Layer↗
PubMed1987

The impact of maternal depression in young children.

An urban working class sample of depressed mothers with two-yr-old children was compared with a control group of non-depressed mothers using maternal interviews, home observation of mother/child interaction, and developmental assessment of the children. Measures were repeated after six months. Children of depressed mothers showed more emotional and behavioural disturbance and delay in expressive language development. Depressed mothers had more past and current adverse experiences, particularly in close relationships. In general depressed mothers were less responsive to their children and less able to sustain social interaction: their children were more often distressed, but there was a big variation in quality of mother/child interaction within the depressed group.

Child Rearing↗
PubMed1987

Communicating with adolescents from culturally varied backgrounds: a model based on Mexican-American adolescents in south Texas.

Health care delivery to Mexican-American adolescents requires knowledge of the general health needs of adolescents, as well as culturally determined beliefs about health and illness. Specific concepts about the cause and treatment of a variety of symptoms may cause some Mexican-American families to seek help from parallel systems of health care (i.e., the curandera and the physician). By understanding the family's beliefs about the problem, the physician can incorporate both systems to enhance a positive outcome. The physician needs to be aware of the extent to which the family both suffers with the ill adolescent patient and contributes to the acquisition of the patient's health. Differences in the extent of acculturation between adolescents and their parents may intensify the common parent-adolescent conflicts seen as a developmental phenomenon. As with any adolescent patient, a thorough history will help to assess the problem and will provide clues as to the best methods for intervention.

Acculturation↗
PubMed1983

Atopic dermatitis. A review of diagnosis, pathogenesis, and management.

Atopic dermatitis, one of the common dermatologic abnormalities encountered by pediatricians in clinical practice, is a chronic pruritic skin disorder occurring in individuals with a personal or family history of atopic disease such as asthma or allergic rhinitis. Atopic dermatitis appears to be an inherited disease, although the mode of inheritance has not been established. Clinically, its course can be divided into stages: infantile, childhood, and adult. Recognition of atopic dermatitis in any of these stages should facilitate appropriate treatment. This general overview examines several aspects of the disease, including current concepts of clinical manifestations, differential diagnosis, pathogenesis, and treatment.

Acute Disease↗