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Biomedical subjects

A Hall

Publications and source records attributed to A Hall.

At least 325 records · Page 18Linked to original sources
PubMed1989

Stimulation of phosphatidylcholine hydrolysis, diacylglycerol release, and arachidonic acid production by oncogenic ras is a consequence of protein kinase C activation.

Swiss-3T3 cells were scrape-loaded with oncogenically activated p21ras protein. 10-20 min after introducing Val12p21ras into the cell, diacylglycerol levels were increased, but levels of inositol phosphates were unaltered. However, cellular choline and phosphocholine levels were increased with a similar time course to that observed for diacylglycerol production, suggesting that ras increases phosphatidylcholine turnover but not phosphatidylinositol turnover. Down-regulation of protein kinase C (by prolonged exposure to phorbol esters prior to scrape loading) blocked the ability of ras protein to elevate the levels of diacylglycerol, choline, and phosphocholine. Oncogenic ras can, therefore, cause a substantial increase in diacylglycerol (which correlates with increased phosphatidylcholine breakdown) in a protein kinase C-dependent fashion. Val12p21ras also increased arachidonic acid release, which was also dependent on protein kinase C activation. Induction of DNA synthesis by oncogenic ras was unaffected by inhibitors of prostaglandin synthesis, indicating that conversion of the released arachidonic acid to various prostaglandins is not required for stimulation of DNA synthesis by ras. We suggest that ras rapidly activates protein kinase C, which in turn activates a number of cellular signalling systems, leading to a sustained increase in diacylglycerol levels. This elevation of diacylglycerol could sustain protein kinase C activation over the 12-15 h required for initiation of DNA synthesis.

Animals↗
PubMed1989

Bombesin stimulation of inositol 1,4,5-trisphosphate generation and intracellular calcium release is amplified in a cell line overexpressing the N-ras proto-oncogene.

Bombesin stimulation of T15 cells in which the inducible N-ras oncogene is overexpressed caused elevated production of inositol phosphates compared to uninduced cells [Wakelam, Davies, Houslay, McKay, Marshall & Hall (1986) Nature (London) 323, 173-176]. This elevated response is shown here to result from increased generation of inositol 1,4,5-trisphosphate leading to an elevated release of intracellular stored Ca2+. Single-cell analysis of Ca2+ release showed that the elevated response is not a consequence of an increased fraction of responding cells. These amplifications are consistent with p21N-ras acting like a guanine nucleotide coupling protein in this cell line.

Bombesin↗
PubMed1989

Scrape-loaded p21ras down-regulates agonist-stimulated inositol phosphate production by a mechanism involving protein kinase C.

The effect of scrape-loaded [Val-12]p21ras on agonist-stimulated phosphatidylinositol 4,5-bisphosphate (PIP2) turnover in Swiss-3T3 cells was studied. Previously [Morris, Price, Lloyd, Marshall & Hall (1989) Oncogene 4, 27-31] we demonstrated that [Val-12]p21ras activates protein kinase C within 10 min of scrape loading. Here, we show that [Val-12]p21ras inhibits bombesin and platelet-derived growth factor-stimulated PIP2 breakdown 1.5-4 h after scrape loading. This effect persisted for at least 18 h and could be mimicked in control cells by activation of protein kinase C with 12-O-tetradecanoyl 13-acetate (TPA) 15 min prior to ligand stimulation. When protein kinase C was down-regulated by chronic TPA treatment, [Val-12]p21ras was no longer able to inhibit agonist-stimulated inositol phosphate production. These results indicate that changes in inositol phosphate levels caused by ras protein are probably due to activation of protein kinase C and not to an interaction of ras with phospholipase C.

Animals↗
PubMed1989

The rho gene product expressed in E. coli is a substrate of botulinum ADP-ribosyltransferase C3.

The ras-related rho A protein expressed in E. coli, was ADP-ribosylated by botulinum ADP-ribosyltransferase C3. C3 also modified the valine-14 mutant rho protein but not the products of H-ras, R-ras, ral, ypt, and rap 1 genes. A ras-rho chimaera consisting of 60 amino acids from the amino terminus of ras fused to 133 amino acids from the carboxy terminus of rho was not modified by C3. Antibodies raised against the porcine brain cytosolic substrate of C3 cross reacted with the rho, valine-14 rho and ras-rho proteins, but not with the gene products of H-ras, R-ras, ral or rap 1. Polyclonal anti-H-ras antibodies cross reacted with H-ras but not with ral, rho, or the C3 substrate purified from porcine brain.

ADP Ribose Transferases↗
PubMed1989

Identification of distinct cytoplasmic targets for ras/R-ras and rho regulatory proteins.

The protein products of the mammalian ras genes, p21ras, are regulatory guanine nucleotide binding proteins that are involved in the control of cell proliferation, though the exact biochemical processes regulated are unknown. Recently a cytoplasmic protein has been identified that interacts with and increases the GTPase activity of p21ras. It has been shown that this GTPase-activating protein, or GAP, interacts with the effector domain of ras, leading us and others to propose that GAP may be the target for regulation by p21ras. It has become apparent that ras is part of a much larger family of proteins, and at least 15 ras-related genes have now been identified in the mammalian genome. Each encodes a small (about 21 kDa) guanine nucleotide binding protein, but the functions of none of these regulatory molecules are known. We report here that mammalian cytoplasmic extracts contain GAP-like activity toward the products of two other ras-related genes, R-ras and rho. It appears that p23R-ras interacts with the same 125-kDa GAP protein as p21ras whereas p21rho interacts with a distinct 29-kDa protein, rho GAP.

Cytoplasm↗
PubMed1989

Signal transduction by p21ras.

Experiments using the physical loading of purified recombinant p21 ras proteins into quiescent normal cells to analyze how the proteins stimulate DNA synthesis and morphological transformation are reviewed. The results indicate that oncogenic p21ras proteins rapidly activate a protein-kinase-C-dependent pathway and a protein-kinase-C-independent pathway. The activation of protein kinase C is absolutely required for p21ras to stimulate DNA synthesis but is not required for morphological transformation.

Animals↗
PubMed1989

p21H-ras-induced morphological transformation and increases in c-myc expression are independent of functional protein kinase C.

It has previously been demonstrated that efficient DNA synthesis by oncogenic p21H-ras only occurs in the presence of insulin and is absolutely dependent on functional protein kinase C. Here we show that morphological transformation induced by oncogenic p21H-ras does not require functional protein kinase C. The early phases of protein kinase C-independent morphological transformation do not require de novo protein synthesis. We have also demonstrated that the introduction of p21H-ras into quiescent Swiss 3T3 cells by scrape-loading leads to increased levels of c-myc mRNA similar to those seen following serum stimulation. The increases in c-myc mRNA levels induced by p21H-ras are also independent of functional protein kinase C. Both morphological transformation and the elevation of c-myc mRNA levels do not require insulin. These results demonstrate that p21H-ras is generating protein kinase C-dependent and -independent signals.

Animals↗
PubMed1989

The reliability and discriminant validity of three potential measures of bulimic behaviours.

There is currently a need for a reliable and valid self-report measure of bulimic behaviours that is brief and economical to administer and that can be used to assess response to treatment and to investigate correlates of bulimic symptoms. Three potential screening measures of bulimic behaviours (the Bulimia Test, the Conroy-Healy Eating Questionnaire and the Bulimia subscale of the Eating Disorder Inventory) were evaluated using internal consistency analysis and Receiver (or Relative) Operating Characteristic curve analysis, to determine their internal reliability and ability correctly to identify bulimic patients seen at an eating disorders outpatients clinic. The results showed that the three measures examined were all good discriminators of bulimic and non-bulimic patients. However, the results showed that the Bulimia Test was clearly the most reliable measure, apparently because of its greater length. It is suggested that further investigations be conducted to establish the sensitivity of the Bulimia Test to changes in the severity of bulimic behaviours in patients, since this will increase knowledge of its utility as a measure of response to treatment.

Adult↗
PubMed1989

Peritoneal cytology in malignant mixed müllerian tumors of the uterus.

Peritoneal cytologic studies (10 ascitic fluids, 18 peritoneal washings) were performed on 28 patients with malignant mixed müllerian tumors of the uterus. The frequency of recovery of malignant cells from the peritoneal cavity was directly related to stage of disease and depth of myometrial invasion. In stage I, positive peritoneal cytology was of greater prognostic importance than depth of invasion: all patients with negative cytology are alive without evidence of disease; all patients with positive cytology are dead.

Adolescent↗
PubMed1989

Mechanisms of drug resistance in acute leukaemia.

The development of resistance to chemotherapeutic agents is a frequent cause of treatment failure in acute myeloid and lymphocytic leukaemia. The mechanisms by which resistance develops in these patients are poorly understood, although a framework for their investigation has been provided by a range of studies using animal and human cell lines as model systems. In this review the basic concepts of drug resistance mechanisms are outlined, with special emphasis on studies using cells obtained from patients with resistant forms of leukaemia.

Acute Disease↗
PubMed1989

Botulinum ADP-ribosyltransferase C3: a new tool to study low molecular weight GTP-binding proteins.

It is well known that certain bacterial toxins, e.g. cholera and pertussis toxins, ADP-ribosylate eukaryotic regulatory proteins. They have become invaluable tools in the study of G protein-linked receptors. Less well appreciated is the fact that certain strains of Clostridium botulinum types C and D produce an ADP-ribosyltransferase, termed C3. This enzyme is structurally and functionally distinct from botulinum neurotoxins C1 and D. Its substrate is the 21 kDa GTP-binding protein rho. Klaus Aktories and Alan Hall explain why C3 is now an important tool in analysing the regulatory function of the ras-related protein rho.

ADP Ribose Transferases↗
PubMed1989

Visual assessment of the multiply handicapped patient.

The visual capabilities of the multiply handicapped and/or developmentally delayed patient are difficult to assess with methods that depend on the patient's subjective responses. Fifty-nine patients with multiple neurological handicaps and unknown visual capabilities were examined using a modified ophthalmic examination which included visual acuity measures using visual evoked potential (VEP) and preferential looking (PL) techniques. Patients ranged in age from 3 to 33 years; median age 9 years. Significant refractive error (in 73%) and strabismus (in 71%) were the most common ocular disorders. Of the 43 patients with a significant refractive error, only 16 (37%) were wearing their proper correction (ranging from -21 to +20 D). In 27 patients the uncorrected refractive error ranged from -10 to +20 D. Binocular acuities (with refractive correction) could be obtained from 56 patients (95%) using a spatial frequency sweep VEP technique, and in 41 patients (70%) using PL grating acuity cards. The VEP and PL grating acuity measures agreed to within 1 octave (a factor of 2 in minimum angle of resolution) in 27 of 41 patients. VEP acuity was 1.1 to 2.7 octaves higher in 12 patients. Grating acuity of at least 6/12 (20/40) was estimated in 12 patients. Residual vision can be measured in "difficult to examine" multiply handicapped patients with VEP and PL techniques.

Adolescent↗
PubMed1989

The sealing ability of injection-moulded thermoplasticized gutta-percha.

The root canals of 120 single rooted teeth were prepared with files and then divided randomly into twelve subgroups. Four operators each filled three of these subgroups, one group with laterally condensed gutta-percha, one group with thermoplasticized gutta-percha with sealer and one group with thermoplasticized gutta-percha without sealer. The fillings were assessed radiographically and a dye penetration test was used to investigate the leakage. The lowest leakage values were found in those canals filled with laterally condensed gutta-percha. The sealing ability of thermoplasticized gutta-percha was enhanced by the use of a sealer. There was greater variation between operators in those groups where thermoplasticized gutta-percha was used.

Dental Leakage↗
PubMed1989

Inhibition by phospholipids of the interaction between R-ras, rho, and their GTPase-activating proteins.

Certain lipids were found to inhibit the interaction between rho and R-ras proteins and their respective GTPase-activating proteins (GAP). Inhibitory lipids were similar for each protein but differed significantly from those previously found to inhibit the interaction between ras protein and GAP activity. These data raise the possibility that ras and related proteins are controlled biologically by interactions between lipids and GAP molecules.

GTP Phosphohydrolases↗
PubMed1989

Stabilization of the p53 transformation-related protein in mouse fibrosarcoma cell lines: effects of protein sequence and intracellular environment.

The transformation-related protein p53 is normally very labile. The stability of p53 is significantly increased in a number of fibrosarcoma cell lines derived from mouse tumors induced by treatment with physical or chemical agents. In many instances, p53 stabilization is correlated with the ability to form a stable complex with the heat shock protein cognate hsc70. We describe a line in which p53 is very stable yet has no detectable interaction with hsc70. The inability to form such a complex probably resides in the primary structure of the endogenous p53, since introduction of other p53 variants into those cells resulted in the appearance of a p53-hsc70 complex. The factors affecting p53 stability were investigated by stable transfection experiments. The results indicated that the primary structure of the p53 protein is a major determinant of its turnover rate; different p53 variants were degraded at distinct and characteristic rates in a number of transformed cell types. However, at least one p53 variant was degraded differently in nontransformed BALB/c-3T3 than in transformed fibrosarcoma cells, demonstrating that the specific cellular environment can also affect the stability of p53.

Animals↗
PubMed1989

Exercise testing soon after myocardial infarction: its relation to course and outcome at one year in patients aged less than 55 years.

A consecutive series of 184 patients aged less than 55 years who had an acute myocardial infarction were enrolled in a study to examine outcome at one year. One hundred of these patients underwent a maximal exercise test six weeks after infarction to evaluate its ability to predict cardiac events. The in-hospital mortality for the series was 7.6% (14 deaths) and the one year mortality for the 170 survivors was 3.8% (seven deaths). During the exercise test 31 patients had angina and 21 had ST depression. During the one year follow up period 39 of 100 patients had angina on exertion, 15 patients underwent coronary artery surgery, three patients had a reinfarction, and one patient died. Angina during the exercise test but not ST segment depression during the exercise test predicted angina on exertion and the need for coronary artery surgery. In the year of follow up angina occurred during everyday exertion in 25 (81%) (95% confidence interval 62 to 92%) of the 31 patients who developed angina during the exercise test and in only 14 (20%) (95% confidence interval 12 to 32%) of 69 patients who did not, and coronary artery surgery was performed in 11 (35%) (95% confidence interval 19 to 54%) of the 31 patients with angina during the exercise test and only four (6%) (95% confidence interval 2 to 15%) of 69 patients without angina. The outcome after myocardial infarction in patients aged less than 55 years was good and the occurrence of angina, but not ST segment depression, during a maximal exercise test six weeks after infarction was an indication for further investigation.

Age Factors↗
PubMed1989

Investigation of osteopaenia in anorexia nervosa.

Sixty-nine female patients, mean age 27.5 years (range 20-40), with a past or current history of anorexia nervosa (DSM III-R) had spinal trabecular bone density assessed by single energy quantitative CT scan. Current exercise and dietary calcium levels were assessed by detailed questionnaires and categorized. A semi-structured interview was used to record weight, menstruation, exercise and dietary calcium intake histories from early adolescence. Serum sex hormones and total calcium assays were measured. Bone density was significantly lower in the patients compared to 31 controls. Bone density was significantly positively correlated with body mass index, and negatively correlated with illness duration and duration of amenorrhoea. Exercise levels, dietary calcium intake and taking an oestrogen pill did not correlate significantly with bone density. Recovered patients did not have osteopaenia but they had shorter illness histories than non-recovered patients. Management to minimise bone loss should focus on weight gain and resumption of normal menstruation.

Adult↗