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Biomedical subjects

M Russell

Publications and source records attributed to M Russell.

At least 73 records · Page 4Linked to original sources
PubMed1996

Signal transduction and the regulation of cell growth.

The need to understand and characterize critical steps controlling mitogenesis is a problem being addressed in many laboratories today. Genetic damage in cancer cells is a universal characteristic, and the search for the targets of this damage has led to the study of numerous complex signal transduction pathways which are involved in regulating cellular proliferation and differentiation. One important signal transduction cascade involved in controlling mitogenesis is the mitogen-activated protein kinase pathway. It is now clear that both tyrosine kinase growth factor receptors and G protein-coupled receptors regulate this pathway. Recent work from many groups has resulted in the initial characterization of the events that lead to mitogen-activated protein kinase activation by these different receptors. This review will contain a brief background of G proteins and their potential role in controlling cell growth.

Animals↗
PubMed1995

Solution conformation of the extracellular domain of the human tumor necrosis factor receptor probed by Raman and UV-resonance Raman spectroscopy: structural effects of an engineered PEG linker.

The solution structure of the Escherichia coli-expressed extracellular domain, residues 12-172, of the human 55 kDa type I tumor necrosis factor receptor (TNFR) has been probed by Raman (514.5 nm) and ultraviolet-resonance Raman (244 nm) excitations. The Raman spectra have been collected from both the free TNFR domain and an engineered "dumbbell-like" derivative, consisting of two mutant receptor moieties linked by a 20 kDa polyethylene glycol (PEG) tether. The results demonstrate a TNFR secondary structure which is rich in beta-sheet and deficient in alpha-helix, consistent with the reported X-ray crystal structure of baculovirus expressed receptor complexed with factor beta [Banner, D. W., D'Arcy, A., Janes, W., Gentz, R., Schoenfeld, H.-J., Broger, C., Loetscher, H., & Lesslauer, W. (1993) Cell 73, 431-445]. Conversely, the solution structure of TNFR differs from the crystal structure in its distribution of disulfide rotamers and in the orientation of its unique indole side chain (tryptophan-107). These differences are attributed, respectively, to N-terminal truncation and factor binding in the TNFR crystal structure. The tryptophan configuration, which is easily monitored in both Raman and UVRR spectra, is proposed as a potential signal of receptor/factor recognition and binding. Application of the Raman probes to the engineered TNFR dumbbell, which is of interest as a potential therapeutic, shows that TNFR moieties of the dumbbell exhibit secondary structures and side chain environments which are indistinguishable from those of the native, wild-type moiety. The results suggest that the PEGylated dumbbell may function as an effective TNFR drug delivery system without the consequence of a deleterious antigenic response.

Amino Acid Sequence↗
PubMed1995

Differential calcium dependence in the activation of c-Jun kinase and mitogen-activated protein kinase by muscarinic acetylcholine receptors in rat 1a cells.

Carbachol stimulation of the muscarinic acetylcholine m1 receptor (m1R), stably expressed in Rat 1a fibroblasts, resulted in a calcium-dependent activation of c-Jun kinase (JNK). Stimulation of the muscarinic acetylcholine m2 receptor (m2R), stably expressed in Rat 1a fibroblasts, resulted in a G1-mediated activation of JNK that was weak relative to that observed with the m1R. Chelation of calcium inhibited the m2R-mediated activation of JNK but not the robust m2R stimulation of mitogen-activated protein kinase (MAPK) activity. These findings demonstrate a role for the second messenger, calcium, in the differential regulation of the activity of JNK and MAPK in Rat 1a cells.

Animals↗
PubMed1995

Regulation of recombinant MEK1 and MEK2b expressed in Escherichia coli.

Mitogen-activated protein kinase (MAPK) activation is an important signal involved in regulating cellular proliferation and/or differentiation. The immediate upstream kinase MAPK kinase, referred to as MEK, activates MAPK by phosphorylation on specific tyrosine and threonine residues. To date, two MEK's have been cloned and characterized, MEK1 and MEK2. Here we report the cloning of MEK2b from mouse pituitary cDNA. Rat and mouse MEK2 amino acid sequences vary by only three amino acids; the three changes are conserved in the MEK1 sequence. Analysis of recombinant MEK2b and MEK1 demonstrated similar activation by upstream kinases and phosphotransferase activity toward MAPK, while they differed in autophosphorylation and the ability to serve as a substrate for MAPK. The findings demonstrate significant differences in potential regulatory mechanisms of MEK1 and MEK2/2b but not in their activation by upstream regulators.

Amino Acid Sequence↗
PubMed1995

Direct interaction between Ras and the kinase domain of mitogen-activated protein kinase kinase kinase (MEKK1).

Mitogen-activated protein kinase kinase kinase (MEKK1) is a serine-threonine kinase that regulates sequential protein kinase pathways involving stress-activated protein kinases and mitogen-activated protein kinases. MEKK1 is activated in response to growth factor stimulation of cells and by expression of activated Ras. We demonstrate that the kinase domain of MEKK1 (MEKKCOOH) binds to GST-RasV12 in a GTP-dependent manner. Purified bacterially expressed MEKKCOOH binds to GST-RasV12(GTP gamma S) (GTP gamma S is guanosine 5'-3-O-(thio)triphosphate), demonstrating a direct interaction of the two proteins. A Ras effector domain peptide blocks the binding of MEKKCOOH to GST-RasV12(GTP gamma S). MEKKCOOH complexed with GST-RasV12(GTP gamma S) is capable of phosphorylating MEK1. These findings indicate that MEKK1 directly binds Ras.GTP. Thus, Ras interacts with protein kinases of both the Raf and MEKK families.

Animals↗
PubMed1995

A BDNF autocrine loop in adult sensory neurons prevents cell death.

During the initial phase of their development, sensory neurons of the dorsal root ganglion (DRG) require target-derived trophic support for their survival, but as they mature they lose this requirement. Because many of these neurons express BDNF (brain-derived neurotrophic factor) messenger RNA, we hypothesized that BDNF might act as an autocrine survival factor in adult DRG neurons, thus explaining their lack of dependence on exogenous growth factors. When cultured adult DRG cells were treated with antisense oligonucleotides to BDNF, expression of BDNF protein was reduced by 80%, and neuronal survival was reduced by 35%. These neurons could be rescued by exogenous BDNF or neurotrophin-3, but not by other growth factors. Similar results were obtained with single-neuron microcultures, whereas microcultures derived from mutant mice lacking BDNF were unaffected by antisense oligonucleotides. Our results strongly support an autocrine role for BDNF in mediating the survival of a subpopulation of adult DRG neurons.

Aging↗
PubMed1995

Acetylcholine muscarinic receptor regulation of the Ras/Raf/MAP kinase pathway.

Acetylcholine muscarinic m1 receptors and m2 receptors are predominantly coupled to the heterotrimeric G proteins Gq, 11 and Gi, respectively. Stimulation of the m1 and m2 receptors in different cell types activate the Ras/Raf/MAP kinase pathway. The ability of the m1 receptor to activate the MAP kinase pathway is dependent on the isoforms of adenylyl cyclase expressed in specific cell types. Specific adenylyl cyclases respond to different signals, including calcium and protein kinase C, with increased cAMP synthesis resulting in protein kinase A activation. Stimulation of protein kinase A inhibits Raf and subsequent MAP kinase activation by G protein-coupled receptors and growth factor receptor tyrosine kinases. G protein-coupled receptors can positively and negatively regulate the responsiveness of tyrosine kinase-stimulated response pathways.

Animals↗
PubMed1995

Drinking to regulate positive and negative emotions: a motivational model of alcohol use.

The present study proposed and tested a motivational model of alcohol use in which people are hypothesized to use alcohol to regulate both positive and negative emotions. Two central premises underpin this model: (a) that enhancement and coping motives for alcohol use are proximal determinants of alcohol use and abuse through which the influence of expectancies, emotions, and other individual differences are mediated and (b) that enhancement and coping motives represent phenomenologically distinct behaviors having both unique antecedents and consequences. This model was tested in 2 random samples (1 of adults, 1 of adolescents) using a combination of moderated regression and path analysis corrected for measurement error. Results revealed strong support for the hypothesized model in both samples and indicate the importance of distinguishing psychological motives for alcohol use.

Adaptation, Psychological↗
PubMed1995

The quality of life of children with chronic epilepsy and their families: preliminary findings with a new assessment measure.

The aim of this study was to develop and validate a new schedule to measure the impact of epilepsy on children and their families. 30 questions assess four aspects of the child's and family's lifestyle: epilepsy and its treatment, impact on the child, impact on the parent and impact on the family. For each question, two dimensions are considered: the frequency of the problem, and its importance or degree of concern that it causes. The questionnaire was piloted on the parents of 21 children with chronic epilepsy attending a seizure clinic. Epilepsy was well controlled in half of the children and poorly controlled in the remainder. The questionnaire discriminated well between the two groups of children. Further research will be undertaken to assess the usefulness of the questionnaire on a larger and more representative group of children with epilepsy.

Adolescent↗
PubMed1995

Correlates of alcohol-related problems in African-American and white gynecologic patients.

The purpose of this study was to assess racial differences in the risk of alcohol-related problems associated with alcohol consumption, regular psychoactive drug use, a family history of alcohol-related problems, sociodemographic factors (age and education), and social roles (work, marital, and parental) among nonabstaining African-American and White gynecologic outpatients. In addition, work, marital, and parental roles were investigated to determine whether they mediated or explained racial differences observed in relationships between these factors and alcohol-related problems. Respondents were 630 African-American women and 769 White women aged 13-77 who were systematically sampled from three obstetric/gynecologic clinics and two private practices in Erie County, New York. Hierarchical multiple regression analysis was used to test the significance of main effects of these factors on alcohol-related problems, to test the interactive effects of race with each factor, and to test the interactive effects of social roles with alcohol consumption, the only factor for which a racial difference was observed in its relationship with alcohol-related problems. Overall, results indicated that correlates of alcohol-related problems were similar for African-American and White women. Higher risk of alcohol-related problems was associated with lower levels of education and lack of work and parental roles. In addition, married women who drank heavily were at higher risk of alcohol-related women who drank heavily were at higher risk of alcohol-related problems than unmarried women who drank heavily.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

A revised Alcohol Expectancy Questionnaire: factor structure confirmation, and invariance in a general population sample.

OBJECTIVE: The alcohol expectancy construct has become prominent in contemporary psychosocial approaches to understanding alcohol use and abuse. In 1980 Brown and colleagues developed the 90-item Alcohol Expectancy Questionnaire (AEQ) to assess experiences. Rohsenow modified this instrument to create the 40-item Alcohol Effects Questionnaire (AEQ-2). In the present study, we replaced the dichotomous response format of the AEQ-2 with a six-point scale to create the AEQ-3. The purpose of the study was to evaluate the AEQ-3 for factor structure confirmation and invariance across gender and race subgroups. METHOD: We administered the AEQ-3 to a large general population sample (N = 1,260). The instrument was self-administered during a structured interview. RESULTS: Confirmatory factor analyses were conducted to test a correlated eight-factor model consisting of six positive expectancies and two negative expectancies. Fit indices revealed that the eight-factor model fit the data moderately well. Furthermore, the fit of the eight-factor model was largely invariant across race and gender subgroups. Nonetheless, factor intercorrelations and modification indices revealed inadequate discriminant validity. CONCLUSIONS: Based on these findings, we cautiously recommend the AEQ-3 as a measure of alcohol expectancies. Specific recommendations and limitations are discussed regarding future use of the AEQ-3.

Adult↗
PubMed1995

Menorrhagia management options.

A prospective study of the management of menorrhagia in new patients presenting to gynaecological outpatients was undertaken at four centres in Northern Ireland and two in Great Britain. 325 patients were enrolled, the majority of whom (87%) had severe menorrhagia. Patients in all six centres were similar in relation to age, marital status, parity, use of contraception and severity of symptoms. 62% of the patients were managed medically, improved and were discharged. The rates of surgical intervention, in particular in women aged less than 40, appeared higher in the Northern Ireland hospitals than Great Britain. There is a need to review and audit current practices in the management of menorrhagia.

Adolescent↗
PubMed1994

Expression of EVI1 in myelodysplastic syndromes and other hematologic malignancies without 3q26 translocations.

The EVI1 gene encodes a zinc-finger, DNA-binding protein originally described as the transforming gene associated with a common ecotropic viral insertion site in myeloid leukemias. Previous studies demonstrated EVI1 expression in human leukemias in cases with 3q26 translocations, but not in normal blood or bone marrow. These studies also suggested an association between EVI1 expression and chromosome 7 deletion (del). Because of this association, we examined expression of EVI1 using RNA polymerase chain reaction (PCR) in patients with myelodysplastic syndromes (MDS) and acute leukemia with and without 3q26 translocations. EVI1 RNA was expressed in 29% of 34 (95% confidence interval, 20% to 50%) patients with the MDS subtypes refractory anemia (RA), refractory anemia with excess blasts (RAEB), or refractory anemia with excess blasts in transformation (RAEB-T). The vast majority of these cases occurred in patients with RAEB and RAEB-T. EVI1 expression was not detected in patients with chronic myelomonocytic leukemia (CMML), normal bone marrow or cord blood, or a variety of other hematologic malignancies. EVI1 RNA was detected in three of 18 patients with acute myelogenous leukemia (AML) and in two of four patients with acute promyelocytic leukemia (APL). Karyotypes showed that only one AML patient had karyotype 3q26 abnormalities, indicating that EVI1 expression is associated with cases that do not have structural abnormalities involving chromosome 3q26. These studies document for the first time the abnormal expression of EVI1 RNA by patients with MDS, and suggest an important role for EVI1 in the pathogenesis or progression of some myeloid malignancies.

Adult↗
PubMed1994

Expression of GTPase-deficient G alpha 16 inhibits Swiss 3T3 cell growth.

Expression of the GTPase-deficient G alpha 16 polypeptide G alpha 16Q212L, a member of the Gq family of heterotrimeric G proteins, constitutively activated phospholipase C beta activity in Swiss 3T3 cells. Expression of G alpha 16Q212L appears to persistently stimulte a low level of protein kinase C activity which also increases protein kinase A activity in Swiss 3T3 cells. Growth of G alpha 16Q212L expressing cells was significantly inhibited relative to wild-type Swiss 3T3 cells. Bombesin-stimulated DNA synthesis was completely inhibited in G alpha 16Q212L expressing clones, whereas the growth responses to platelet-derived growth factor (PDGF) and serum were inhibited 50-80% relative to wild-type cells. In addition to the inhibition of cell growth, G alpha 16Q212L expression significantly inhibited the stimulation of protein kinase C, Raf-1, MEK, mitogen-activated protein kinase, phospholipase A2 activity, and Ca2+ mobilization in response to PDGF. In contrast, PDGF receptor activation of phospholipase C gamma, phosphatidylinositol 3-kinase, and Ras GTP loading was similar in wild-type and G alpha 16Q212L expressing clones. PDGF regulation of membrane ruffling and actin fiber assembly, responses mediated in part by phosphatidylinositol 3-kinase, were unaffected in G alpha 16Q212L expressing clones. The growth inhibitory action of G alpha 16Q212L expression in Swiss 3T3 cells is downstream of the initial SH2 domain-encoded signal transduction proteins regulated in response to PDGF receptor autophosphorylation. The findings demonstrate that constitutively activated G alpha 16Q212L persistently activates phospholipase C activity and effectively inhibits a subset of cytoplasmic signal transduction pathways involved in growth factor tyrosine kinase receptor stimulation of cell growth. G16/Gq-regulated signal transduction can acutely stimulate specific response pathways involved in mitogenesis; but persistent activation of G16/Gq-regulated effectors, including phospholipase C beta, inhibit tyrosine kinase-initiated mitogenesis. One role for G16/Gq response systems may be to modulate growth factor receptor signaling.

3T3 Cells↗
PubMed1994

How does the G protein, Gi2, transduce mitogenic signals?

Serpentine receptors coupled to the heterotrimeric G protein, Gi2, are capable of stimulating DNA synthesis in a variety of cell types. A common feature of the Gi2-coupled stimulation of DNA synthesis is the activation of the mitogen-activated protein kinases (MAPKs). The regulation of MAPK activation by the Gi2-coupled thrombin and acetylcholine muscarinic M2 receptors occurs by a sequential activation of a network of protein kinases. The MAPK kinase (MEK) which phosphorylates and activates MAPK is also activated by phosphorylation. MEK is phosphorylated and activated by either Raf or MEK kinase (MEKK). Thus, Raf and MEKK converge at MEK to regulate MAPK. Gi2-coupled receptors are capable of activating MEK and MAPK by Raf-dependent and Raf-independent mechanisms. Pertussis toxin catalyzed ADP-ribosylation of alpha i2 inhibits both the Raf-dependent and -independent pathways activated by Gi2-coupled receptors. The Raf-dependent pathway involves Ras activation, while the Raf-independent activation of MEK and MAPK does not involve Ras. The Raf-independent activation of MEK and MAPK most likely involves the activation of MEKK. The vertebrate MEKK is homologous to the Ste11 and Byr2 protein kinases in the yeast Saccharomyces cerevisiae and Schizosaccharomyces pombe, respectively. The yeast Ste11 and Byr2 protein kinases are involved in signal transduction cascades initiated by pheromone receptors having a 7 membrane spanning serpentine structure coupled to G proteins. MEKK appears to be conserved in the regulation of G protein-coupled signal pathways in yeast and vertebrates. Raf represents a divergence in vertebrates from the yeast pheromone-responsive protein kinase system.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗