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Biomedical subjects

N Holbrook

Publications and source records attributed to N Holbrook.

12 recordsLinked to original sources
PubMed2000

HuR regulates p21 mRNA stabilization by UV light.

Expression of the cyclin-dependent kinase inhibitor p21 is highly induced by many stresses, including exposure to short-wavelength UV light (UVC), which increases p21 mRNA stability. Investigation into the mechanisms underlying this stabilization process revealed that proteins present in cytoplasmic lysates of human RKO colorectal carcinoma cells formed complexes with p21 mRNA that were inducible by treatment with UVC and other stress agents. The ubiquitous Elav-type RNA-binding protein HuR was identified within the p21 mRNA-protein complexes, as antibodies recognizing HuR supershifted these complexes and revealed HuR-immunoreactive proteins complexing with p21 mRNA on Western blots. Lowering of endogenous HuR levels through expression of antisense HuR decreased p21 RNA-protein complexes, greatly reduced the UVC inducibility and half-life of p21 mRNA, and prevented UVC-mediated induction of luciferase activity in p21 3' untranslated region-containing reporter constructs. Our findings indicate that HuR plays a major role in regulating stress-induced p21 expression by enhancing p21 mRNA stability and that these effects are coupled to HuR's elevated presence in the cytoplasm.

Antigens, Surface↗
PubMed1999

Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation.

Responses to increased oxidative stress may be the common mechanism responsible for the varied cytopathology of Alzheimer disease (AD). A possible link in support of this hypothesis is that one of the most striking features of AD, the abnormal accumulation of highly phosphorylated tau and neurofilament proteins, may be brought about by extracellular receptor kinase (ERK) whose activation is a common response to oxidative stress. In this study, we demonstrate that activated ERK is specifically increased in the same vulnerable neurons in AD that are the site of oxidative damage and abnormal phosphorylation. These findings suggest that ERK dysregulation, likley resulting from oxidative stress, could play an important role in the increased phosphorylation of cytoskeletal proteins observed in AD.

Adult↗
PubMed1998

Cat allergen levels in public places in New Zealand.

AIMS: Cat allergen (Fel d 1) is a known risk factor for asthma. Studies have demonstrated Fel d 1 in both public buildings and domestic dwellings where cats have never been. The aims of this study were to measure reservoir Fel d 1 levels in public buildings in New Zealand, to examine determinants of these levels and to compare them with previously measured domestic levels. METHODS: Dust was obtained in two centres (Wellington and Christchurch) from hotels, hospitals, rest homes, churches, primary schools, childcare centres, cinemas, bank head offices and aeroplanes; and from North Island ski lodges. Measurements of temperature and relative humidity were taken. Information was collected on building characteristics. Fel d 1 levels (microg/g of fine dust) for floors (n=203), beds (n=64) and seats (n=24) were expressed as geometric means (95% confidence intervals). RESULTS: Detectable Fel d 1 levels were found in 95% of floor samples, 91% of bed samples and 100% of seat samples. Fel d 1 levels [geometric mean (95% confidence intervals)] were significantly higher on cinema and domestic aircraft seats [36.8 (20.8-65.3) microg/g and 33.3 (28.0-39.7) microg/g respectively] than on floors [3.6 (2.5-5.1) microg/g and 2.4 (1.8-3.0) microg/g respectively]. Floor Fel d 1 levels in the public buildings sampled were lower than those of domestic dwellings without cats [0.9 (0.6-1.4) microg/g vs 1.7 (1.2-2.4)] microg/g in Wellington and [2.0 (1.6-2.6) microg/g vs 4.0 (2.7-6.0] microg/g in Christchurch. After controlling for potential confounders, floor Fel d 1 levels were higher with carpeted floors (p<0.001) and lower in banks and hospitals (p<0.001). CONCLUSION: Fel d 1 levels in public buildings are low in New Zealand public places except for cinema and domestic aircraft seats where all but one sample had Fel d 1 levels potentially high enough to precipitate asthma symptoms in sensitised individuals.

Air Pollution, Indoor↗
PubMed1997

House dust mite allergen levels in public places in New Zealand.

BACKGROUND: House dust mite allergens are a risk factor for asthma in New Zealand, and levels in domestic dwellings have been found to be high compared with levels in most other countries. Studies in other countries have demonstrated lower levels of Dermatophagoides pteronyssinus allergens in public places compared with levels in domestic dwellings. OBJECTIVES: The purpose of this study was to measure reservoir Der p 1 levels in public places in New Zealand and to examine determinants of these levels. METHODS: Reservoir dust was obtained in the two centers (Christchurch and Wellington) from hotels, hospitals, rest homes, churches, primary schools, childcare centers, cinemas, bank head offices, and airplanes; samples were also obtained from ski lodges. Single measurements of temperature and relative humidity were taken with thermohygrometers and an average humidity over 2 weeks was estimated with use of waxed wooden sticks. Information was collected on building construction, type of heating, and frequency of cleaning. Der p 1 levels (micrograms per gram of fine dust) for floor (n = 202), bed (n = 65), and seat (n = 24) samples in public places were expressed as geometric means (95% confidence intervals). RESULTS: Der p 1 levels in public places were significantly lower than domestic levels in both Wellington and Christchurch. Both floor and bed levels were higher in hotels than in other public places. After controlling for potential confounders, floor Der p 1 levels were higher with carpeted floors (p < 0.0001) and lower with recent cleaning (p = 0.02) and bed Der p 1 levels were higher with timber wall construction (p = 0.03). Other building, heating, or cleaning characteristics did not show significant association with allergen levels. CONCLUSION: Der p 1 levels were much lower in public places than in domestic dwellings with floor levels primarily affected by floor covering.

Allergens↗
PubMed1997

Evaluation of a self-management plan for chronic obstructive pulmonary disease.

We hypothesized that the use of an Action Plan might assist self-management for patients with chronic obstructive pulmonary disease (COPD). A pilot process and randomized, controlled study were undertaken to evaluate an Action Plan that provided advice on management of usual care and exacerbations, together with a booklet on self-management. Fifty six subjects with COPD recruited through general practitioners (GPs) completed the 6 month study, 27 in the control group and 29 in the intervention group. The control group received usual care from their GP, and the intervention group received a booklet and Action Plan from their practice nurse plus a supply of prednisone and antibiotic from their GP. The two groups were demographically similar with a mean age of 68 yrs. The resources were well received by GPs, practice nurses and intervention group subjects. After 6 months, there were no differences in quality of life scores or pulmonary function. There were significant changes in self-management behaviour in the intervention group compared to controls. In response to deteriorating symptoms, 34 versus 7% (p=0.014) initiated prednisone treatment and 44 versus 7% (p=0.002) initiated antibiotics. Subjects in the intervention group readily adopted self-management skills but did not show any difference in quality of life or lung function parameters. A larger, prospective, controlled, clinical trial of this approach is warranted.

Aged↗
PubMed1993

Responsibility.

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Ethics, Nursing↗
PubMed1991

Immediate and delayed molecular response of human keratinocytes to solar-simulated irradiation.

The clinical and histologic events in human skin after a single ultraviolet exposure are well documented; and both in vitro and in vivo studies have established immunologic and mutagenic effects of ultraviolet rays on cells. However, little is known about the ultraviolet damage/repair response at the level of gene induction. This study examines the genetic response in cultured human keratinocytes exposed to a single solar-simulated ultraviolet dose and harvested at 1, 4, 8, 24, and 48 hours postirradiation for northern blot analysis using c-DNA probes to well studied stress related genes, heat shock protein 70 and ubiquitin; to a recently cloned gene associated with growth arrest and DNA damage (gadd 153); to c-myc and c-fos, two proto-oncogenes known to be associated with cell growth and differentiation; and to glyceraldehyde phosphate dehydrogenase, known to be involved in cellular intermediary metabolism, gadd 153 and c-fos mRNA levels are increased early (1-4 hours) in keratinocytes, at a time when the cells appear indistinguishable from nonirradiated controls. At the same early time points, the c-myc mRNA level is decreased. Heat shock protein 70 and ubiquitin transcripts are detectable under basal conditions but are not increased by ultraviolet exposure; although at later time points (24-48 hours), when there is morphologic evidence of cell damage and downregulation of the otherwise constitutively expressed gene glyceraldehyde phosphate dehydrogenase, their unchanged steady state levels of mRNA constitute relative over expression. Irradiation of cells with the same solar-simulated ultraviolet dose filtered to remove the shortest and most damaging wavelengths results in a similar pattern of early gene induction, even though cell growth and survival are unaffected. These data suggest that two classes of genes participate in the response to ultraviolet rays: early genes whose mRNA levels are increased (gadd 153, c-fos) or decreased (c-myc) before or independent of any morphologic evidence of cell damage and late genes that are relatively increased (heat shock protein 70, ubiquitin) or decreased (glyceraldehyde phosphate dehydrogenase) in expression when morphologic cell damage is present. The early events may be a direct response to ultraviolet irradiation, whereas the late events may represent a secondary response to stress.

Base Sequence↗
PubMed1989

Distinct factors bind the AP-1 consensus sites in gibbon ape leukemia virus and simian virus 40 enhancers.

We have demonstrated that the gibbon ape leukemia virus (GALV) enhancer AP-1 element and the simian virus 40 AP-1 enhancer element bind different factors in HeLa nuclear extracts. A 39-kilodalton HeLa nuclear protein and the c-fos protein bind to the GALV element. Antibodies to c-fos abolish binding to the GALV AP-1 site. In contrast, anti-c-fos immunoglobulin fails to inhibit formation of the simian virus 40-specific complex from extracts of HeLa cells. Thus, AP-1-binding complexes are subject to compositional variation at different binding sites.

Animals↗
PubMed1987

Activation of interleukin 2 and interleukin 2 receptor (Tac) promoter expression by the trans-activator (tat) gene product of human T-cell leukemia virus, type I.

Cotransfection of cDNA encoding the trans-activator gene product of human T-cell leukemia virus, type I (HTLV-I) (tat-I), which acts in trans to augment viral gene expression, has revealed strong regulatory effects of this viral protein on the inducible cellular promoters governing human interleukin 2 (IL-2) and IL-2 receptor (Tac) gene expression. The tat-I protein stimulates a 3- to 6-fold increase in IL-2 receptor (Tac) promoter activity in transfected Jurkat T cells, but not in the natural killer-like YT cell line, as measured by changes in the expression of the chloramphenicol acetyltransferase (CAT; EC 2.3.1.28) reporter gene linked to this promoter. In contrast, tat-I alone has little or no effect on IL-2 promoter activity in Jurkat T cells but markedly synergizes with other mitogenic stimuli (phytohemagglutinin, phorbol 12-myristate 13-acetate, or the OKT3 monoclonal antibody), which alone are ineffective. The tat-I protein also partially circumvents the pronounced inhibitory effects of cyclosporin A on the IL-2 promoter. Other cellular and viral promoters are unaffected by the tat-I gene product, either alone or in combination with other mitogens. The specific effects of the tat-I gene product on the IL-2 and IL-2 receptor (Tac) promoters suggest the possibility of an autocrine or paracrine mechanism of T-cell growth as an early event in HTLV-I-mediated leukemogenesis.

Acetyltransferases↗
PubMed1987

Binding of a cellular protein to the gibbon ape leukemia virus enhancer.

The gibbon ape leukemia virus (GALV) contains enhancer activity within its long terminal repeat. In the GALV Seato strain this activity resides in a 48-base-pair (bp) repeated element. We demonstrate the existence of a cellular protein which binds in this region of the Seato strain. A sensitive method for enriching protein-DNA complexes from crude extracts coupled with exonuclease and DNase footprint analysis revealed the specific binding of this protein to a 21-bp region within each repeated element. A 22-bp oligonucleotide fragment defined solely by the 21-bp footprint binds a protein in vitro and displays enhancer activity in vivo, suggesting that this protein is a major determinant of GALV enhancer activity. The protein is present in three cell lines which are positive for enhancer activity and is not detected in Jurkat cells, which are negative for enhancer activity. Only GALV long-terminal-repeat variants which support high levels of enhancer activity in vivo compete with this protein for specific binding in vitro, suggesting a potential role for the protein in determining enhancer activity. This protein binding is not inhibited by competition with heterologous retroviral enhancers, demonstrating that it is not a ubiquitous retroviral enhancer binding protein.

Animals↗
PubMed1987

Regulation of interleukin 2 and interleukin 2 receptor gene expression in human T cells: I. Effect of Ca2+-ionophore on phorbol myristate acetate co-stimulated cells.

Human peripheral blood T lymphocytes were treated with phorbol myristate acetate (PMA), an activator of protein kinase C (PKC) activity, and with the calcium ionophore A23187. The resulting accumulation of specific mRNA for interleukin 2 (IL-2) and interleukin 2 receptor (IL-2R), as well as IL-2 secretion and membrane IL-2R expression were examined. At low concentrations (0.1 microM), A23187 synergized maximally with PMA to induce proliferation, to increase IL-2R mRNA levels and the expression of membrane IL-2R, and to produce a low but sufficient accumulation of IL-2 mRNA and IL-2 secretion. A high concentration of A23187 (1.0 microM) did not show any synergism for the accumulation of IL-2R mRNA, membrane IL-2R expression and inhibited the proliferation of PMA co-stimulated T cells. It did, however, induce maximum accumulation of IL-2 mRNA and IL-2 secretion.

Calcimycin↗