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J M Paterson

Publications and source records attributed to J M Paterson.

33 records · Page 2Linked to original sources
PubMed1995

Calcineurin feedback inhibition of agonist-evoked cAMP formation.

The effects of immunosuppressant blockers of calcineurin (protein phosphatase 2B) on cAMP formation and hormone release were investigated in mouse pituitary tumor (AtT20) cells. Immunosuppressants enhanced corticotropin-releasing factor- and isoproterenol-evoked cAMP production in proportion with their potency to block calcineurin. Further analysis of cAMP production revealed that intracellular Ca2+ derived through voltage-regulated calcium channels reduces cAMP formation induced by corticotropin releasing-factor or beta 2-adrenergic stimulation and that this effect of Ca2+ is inhibited by blockers of calcineurin. AtT20 cells were found to express at least three species of adenylyl cyclase mRNA-encoding types 1 and 6 as well as a novel isotype, which appeared to be the predominant species. In two cell lines expressing very low or undetectable levels of the novel cyclase mRNA (NCB20 and HEK293 cells respectively), corticotropin-releasing factor-induced cAMP formation was not altered upon blockage of calcineurin activity. These data identify calcineurin as a Ca2+ sensor that mediates the negative feedback effect of intracellular Ca2+ on receptor-stimulated cAMP production. Furthermore, the effect of calcineurin on cAMP synthesis appears to be associated with the expression of a novel adenylyl cyclase isotype, which is highly abundant in AtT20 cells.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Control of a novel adenylyl cyclase by calcineurin.

The molecular complex formed by the immunosuppressant FK506 and the immunophilin protein FKBP12 potently inhibits the Ca2+/calmodulin-activated protein phosphatase calcineurin. This mechanism appears to be common to all types of cell, implying that fundamental physiological modes of calcineurin regulation are exploited by immunosuppressants. The present paper describes a novel adenylyl cyclase regulated by calcineurin that contains an FKBP12-like domain and may thus constitute a physiologically relevant calcineurin docking site mimicked by immunosuppressant-immunophilin complexes. The enzyme messenger RNA is particularly enriched in the cerebral cortex, striatum and hippocampus, where it is localized to neuronal perikarya, indicative of an important role in neuronal function.

Adenylyl Cyclases↗
PubMed1995

An upstream stimulatory factor (USF) binding motif is critical for rat preprotachykinin-A promoter activity in PC12 cells.

We demonstrate the presence of a functional E box motif in the proximal rat preprotachykinin-A (rPPT) promoter. This element (spanning nucleotides -67 to -47) exhibits the sequence 5'-CACGTG-3' which is recognized and bound by the basic helix-loop-helix family of regulatory proteins. We also show that at least one of the factors bound to this rPPT promoter element in both HeLa and PC12 nuclear extract is the ubiquitously expressed transcription factor, the upstream stimulatory factor (USF). Mutation of this element by insertion of a 10 bp linker into the E box motif, in an rPPT promoter fragment spanning -865 to +92, destroys the ability of this promoter fragment to support reporter gene expression in a PC12 cell model of rPPT promoter activity. The data indicate that this rPPT E box element is likely to function as an important cis-regulatory domain in the rPPT promoter.

Animals↗
PubMed1995

Characterisation of a functional E box motif in the proximal rat preprotachykinin-A promoter.

Three E box motifs, which are upstream of the major transcriptional start site, have previously been characterised in the rat preprotachykinin-A (rPPT) promoter. Only one of these, in the proximal promoter spanning nucleotides -67 to -47, has been demonstrated to support reporter gene expression in clonal cell lines under basal growth conditions. Here we demonstrate that the reporter gene expression can be further induced by the action of phorbol 12-myristate 13-acetate (TPA) and nerve growth factor (NGF), respectively, in both HeLa and the neuronally derived PC12 cells. This response is due to the E box motif and not an overlapping consensus sequence for a putative AP1 element, a class of element previously demonstrated to respond to both TPA and NGF in these cell lines. Finally, we demonstrate that this E box motif can support similar levels of reporter gene expression in primary cultures of dorsal root ganglion neurons as observed in clonal cell lines, demonstrating that E box binding complexes can (1) function as a transcriptional regulator in dorsal root ganglion neurons and (2) bind to and therefore presumably regulate rPPT promoter activity.

Animals↗
PubMed1995

Repression of preprotachykinin-A promoter activity is mediated by a proximal promoter element.

The rat preprotachykinin-A promoter, which is able to direct reporter gene expression in adult dorsal root ganglia neurons grown in culture, has no detectable activity in HeLa and PC12 cells. DNAase 1 footprinting and electrophoretic mobility shift analyses with HeLa nuclear extract indicated the presence of a protein complex binding to a region of the rat preprotachykinn-A gene promoter between the TATA box and the major transcriptional start site. We demonstrate that the sequence of the preprotachykinin-A promoter spanning nucleotides -47 to +92 functions to repress reporter gene expression in HeLa and PC12 cells but not in adult rat dorsal root ganglia grown in culture, and that this repression is correlated with a protein(s) binding to the element between the TATA box and major transcription initiation site. These results indicate that the tissue-specific expression of the preprotachykinin-A gene could require the interaction of both positive and negative regulatory DNA elements.

Animals↗
PubMed1995

Three immediate early gene response elements in the proximal preprotachykinin-A promoter in two functionally distinct domains.

The preprotachykinin-A promoter contains two blocks of DNA sequence, with a high degree of homology to one another, both containing activator protein 1/cAMP response element-like elements which constitute cis-acting regulatory domains. These two domains are differentially regulated in HeLa cells and primary cultures of dorsal root ganglion neurons when they are placed in the context of a reporter gene driven by the c-fos minimum promoter. One of the domains, corresponding to a region of the preprotachykinin promoter spanning nucleotides -345 to -308, contains two activator protein 1 elements adjacent to an E-box binding protein consensus sequence. Both of the activator protein 1 elements can bind a complex containing c-fos/c-fos related antigen proteins and the adjacent E-box element is specifically recognized by proteins present in HeLa nuclear extract. This domain requires the synergistic action of both activator protein 1 elements to drive expression of the reporter gene in both HeLa and dorsal root ganglion cells. The second or proximal domain spans nucleotides -198 to -155 and contains a previously characterized activator protein 1/cAMP response element/ATF enhancer element which, in contrast to the activator protein 1 elements in the distal domain, functions in both HeLa and dorsal root ganglion cells as one copy. This domain is differentially regulated in HeLa and dorsal root ganglia. The previously characterized enhancer activity is repressed in the context of the extended cis-acting domain in HeLa cells but remains active in dorsal root ganglion, although no further enhancement of activity supported by the single enhancer is observed when in the context of the extended sequence. This proximal domain, in addition to binding the enhancer complex, can be bound by at least two other complexes, one of which binds to an E-box consensus sequence. As the elements corresponding to the E-box consensus in both domains cross-compete for binding of specific complex(es) it would appear that repression of the activity of the proximal domain is correlated with a specific protein complex binding adjacent to the characterized enhancer in the region spanning nucleotides -198 to -155. The preprotachykinin-A proximal promoter is therefore bound by multiple activator protein I complexes, which in the context of the cis-acting domains in which they are present can be differentially regulated. In the proximal domain their function may also be regulated in a tissue-specific manner by other proteins which bind to adjacent regulatory elements.

Animals↗
PubMed1995

Transcriptional control of neuropeptide gene expression in sensory neurons, using the preprotachykinin-A gene as a model.

Control of neuropeptide gene expression in sensory neurons is determined in part by a variety of tissue-specific, developmental, and stimulus-induced transcription factors that interact with the promoters of these genes. We have analysed the regulation of the rat preprotachykinin-A (rPPT) gene, which is expressed in a subset of dorsal root ganglia neurons. A region of the promoter encompassing approximately 1300 base pairs spanning the transcriptional start site has been analysed in detail both by functional analysis of promoter activity in clonal cell lines and dorsal root ganglia neurons grown in culture and by in vitro characterisation of transcription factor interaction with this region. Interestingly our analysis indicates an important role in rPPT gene expression for the E box transcription factor family. This class of transcription factor has been demonstrated to be a major determinant of calcitonin gene related peptide (CGRP) expression, which is also expressed in dorsal root ganglia neurons often under similar conditions as rPPT. In addition, multiple regulatory domains have been identified in the rPPT promoter, which act as activators in a variety of cell types. These elements are silenced in the context of the rPPT promoter in many non-neuronal cells. Therefore, tissue-specific expression of reporter genes directed by the rPPT promoter in transient transfection is determined in part by a variety of silencer elements, which act to repress the function of several domains that act as constitutive enhancers of expression in a wide range of cells. Removal or modulation of silencer elements in the rPPT promoter allows activity in a wider variety of cell types. We postulate that control of rPPT gene expression is the results of dynamic interplay of both positive and negative regulatory elements, a phenomenon observed in several other neuronal-specific genes, including that encoding CGRP.

Animals↗
PubMed1993

Olecranon spur.

Full extension of the elbow is normally made possible by accommodation of the olecranon within an appropriately shaped fossa in the distal humerus. We report three cases where disability has resulted from an abnormally shaped olecranon.

Adolescent↗
PubMed1993

Redisplacement after manipulation of distal radial fractures in children.

We reviewed 68 fractures of the distal radius in children, all treated by primary manipulation and plaster immobilisation. Complete displacement of the fracture and failure to achieve a perfect reduction were both associated with a significant increase in the chance of redisplacement. We recommend the use of percutaneous Kirschner wires to maintain a satisfactory position in all cases in which a perfect reduction cannot be achieved.

Adolescent↗
PubMed1990

Femoral osteotomy in Perthes' disease. Results at maturity.

Upper femoral osteotomy is a recognised treatment for selected patients with Perthes' disease. The results of this procedure were investigated at skeletal maturity in 44 patients (48 hips). The indication for operation was Catterall group II, III, and IV hips with 'head-at-risk' signs. Harris and Iowa scores were calculated clinically, and each hip was assigned radiographically to one of the five Stulberg classes, its initial Catterall grading checked and other relevant indices measured. Results showed excellent clinical function. Shortening was present in 14 hips (29%) and a positive Trendelenburg's sign was seen in 12 (25%). On radiographic assessment 58% of hips were Stulberg class I or II, with a good prognosis. The results of femoral osteotomy were better than those for conservatively treated hips in all age groups except those under five years.

Adolescent↗
PubMed1990

The Roper-Day total shoulder replacement.

A simple unconstrained shoulder prosthesis has been used in 22 patients (25 shoulders) with incapacitating pain and severely damaged joints who, because of age or generalised rheumatoid disease, have limited functional requirements. All reported good and lasting pain relief. Improvement in range of movement was modest, but there was marked improvement in function. In this group of patients, rotator cuff damage is common, but does not preclude a satisfactory result.

Activities of Daily Living↗
PubMed1989

Walking ability and ankle systolic pressures: observations in patients with intermittent claudication in a short-term walking exercise program.

Walking ability and limb hemodynamics were studied in 56 patients with intermittent claudication in an exercise program. Patients walked 1 hour 3 times a week for 3 to 6 months. Ankle and brachial pressures were measured at rest and after a standard walk, and walking ability on the treadmill and during free walking was determined. Average maximal distance on the treadmill increased from 0.59 to 1.00 km after training (p less than 0.0001). Also, after training 84% of patients were able to walk continuously more than 2 km without severe discomfort. The attained walking ability of individual patients could not be predicted from pressure measurements. Small pressure changes after training suggested that factors other than increased development of collateral vessels were important in determining walking ability. Practically useful walking ability was achieved in patients with aortoiliac and femoropopliteal arterial obstruction in the presence or absence of coronary disease and in patients taking beta-blockers. The results indicate that walking exercise is a valuable treatment for many patients with claudication who are not candidates for arterial reconstruction.

Ankle↗
PubMedDate not supplied

Lower limb lengthening by a modified Wagner technique.

A series of 50 patients who underwent femoral and tibial lengthenings using the Wagner apparatus is reviewed. Satisfactory gains in leg length with an acceptably low complication rate were achieved. Both substitution of cortical osteotomy for complete osteotomy and delaying of distraction increased callus formation. The particular problems of lengthening the congenital short femur and tibia are discussed.

Adolescent↗