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Biomedical subjects

J C Bell

Publications and source records attributed to J C Bell.

At least 37 records · Page 2Linked to original sources
PubMed1998

The murine PKR tumor suppressor gene is rearranged in a lymphocytic leukemia.

The double-stranded RNA-dependent kinase, PKR, is encoded by an interferon inducible gene and is largely responsible for the anti-viral effects of this cytokine. Recent studies have shown that PKR may also play a role in the regulation of normal cellular growth. Although numerous examples of viral strategies for inactivation of PKR exist, there is no evidence of PKR inactivation in tumors. We demonstrate here that the Tik gene, which encodes a dual-specificity kinase, is the murine homolog of PKR, the dsRNA-dependent kinase, and has undergone a rearrangement of one allele in a murine lymphocytic leukemia cell. We have cloned a cDNA that corresponds to a mutated transcript from the rearranged mPKR gene and show that while the mutated polypeptide retains its ability to dimerize and bind dsRNA, it is catalytically inactive. Although this mutated mPKR lacks apparent dominant-negative function, the net effect of reduced PKR activity in these cells may be significant.

Alleles↗
PubMed1998

The Clk2 and Clk3 dual-specificity protein kinases regulate the intranuclear distribution of SR proteins and influence pre-mRNA splicing.

The three members of the Clk family of kinases (Clk1, 2, and 3) have been shown to undergo conserved alternative splicing to generate catalytically active (Clk) and inactive (ClkT) isoforms. The prototype, murine Clk1 (mClk1), is a nuclear dual-specificity kinase that can interact with, and cause the nuclear redistribution of, SR proteins. In this study, we demonstrate that the human Clk2 and Clk3 (hClk2 and 3) are also found within the nucleus and display dual-specificity kinase activity. The truncated isoforms, hClk2(T) and hClk3(T), colocalize with SR proteins in nuclear speckles. We also show catalytically active hClk2 and hClk3 cause the redistribution of SR proteins and can regulate the alternative splicing of a model precursor mRNA substrate in vivo.

Animals↗
PubMed1997

Trends in colorectal cancer incidence and mortality in New South Wales, 1973-1992.

OBJECTIVE: To assess changes in incidence and mortality rates of colorectal cancer in different age groups in New South Wales (NSW) between 1973 and 1992. DESIGN: Descriptive analysis of data on incidence and mortality from the population-based NSW Central Cancer Registry and on colorectal cancer diagnostic tests from the Health Insurance Commission. MAIN OUTCOME MEASURES: Age-standardised incidence and mortality rates for colon and rectal cancer (defined by codes 153 and 154 in the International classification of diseases, 9th revision) by sex and age group (15-44, 45-59, 60-74 or > or = 75 years) and incidence by cancer spread at diagnosis; age-standardised rates for faecal occult blood tests, sigmoidoscopy and colonoscopy. RESULTS: From 1973 to 1992, colorectal cancer incidence increased significantly in NSW by an average of 2.0% per year in males (95% confidence interval [CI], 1.8 to 2.3) and 0.9% in females (95% CI, 0.7 to 1.1). Mortality rates remained nearly constant in males, but fell significantly in females by an average of -1.0% per year (95% CI, -1.3 to -0.7). In the youngest age group (15-44 years) both incidence and mortality rates fell significantly, while rates were stable or rose in older age groups, except for a significant fall in mortality in women aged > or = 75 years. Use of colonoscopy (an early detection method) increased, but a corresponding shift to detection of earlier-stage cancers was not seen. CONCLUSIONS: A reduction in risk factors and better treatment leading to longer survival may have contributed to the falls in incidence in younger people and in mortality in females.

Adolescent↗
PubMed1997

Effect of enucleation on protein synthesis during maturation of bovine oocytes in vitro.

The role of the nucleus in protein synthesis reprogramming during oocyte maturation was examined in immature or mature bovine oocytes, enucleated at the germinal vesicle (GV) stage or the metaphase II (MII) stage. Cumulus-oocyte complexes (COCs) were denuded before or after maturation in vitro. Denuded oocytes were (i) enucleated at the GV or MII stage (after DNA staining and ultraviolet (UV) exposure), (ii) stained and exposed to UV but not enucleated, or (iii) used as controls. After treatment, oocytes were labelled for 4 h with 35S-methionine or were matured for 24 h before labelling. GV- or MII- karyoplasts and small portions of cytoplasm (cytoplasts), removed during enucleation, were also labelled. Labelled oocytes, karyoplasts or cytoplasts were prepared for one-dimensional polyacrylamide gel electrophoresis. Incorporation of labelled methionine into oocyte protein was measured. Enucleation did not affect protein synthesis reprogramming, but incorporation of 35S-methionine in immature UV-stained oocytes was high--possibly due to nuclear repair mechanisms. Protein profiles of GV- and MII- karyoplasts differed from those of immature and mature oocytes. In conclusion, normal protein synthesis reprogramming in the cytoplasm can occur in the absence of the nucleus, and specific proteins are synthesized in the nuclear region.

Animals↗
PubMed1997

In vivo regulation of alternative pre-mRNA splicing by the Clk1 protein kinase.

Controlled expression of cellular and viral genes through alternative precursor messenger RNA (pre-mRNA) splicing requires serine/arginine-rich (SR) proteins. The Clk1 kinase, which phosphorylates SR proteins, is regulated through alternative splicing of the Clk1 pre-mRNA, yielding mRNAs encoding catalytically active and truncated inactive polypeptides (Clk1 and Clk1T, respectively). We present evidence that Clk1 and Clk1T proteins regulate the splicing of Clk1 and adenovirus pre-mRNAs in vivo. The peptide domain encoded by the alternatively spliced exon of Clk1 is essential for the regulatory activity of the Clk1 kinase. This is the first direct demonstration of an in vivo link between alternative splicing and protein kinase activity.

Adenovirus E1A Proteins↗
PubMed1996

The Clk/Sty protein kinase phosphorylates SR splicing factors and regulates their intranuclear distribution.

Mammalian Clk/Sty is the prototype for a family of dual specificity kinases (termed LAMMER kinases) that have been conserved in evolution, but whose physiological substrates are unknown. In a yeast two-hybrid screen, the Clk/Sty kinase specifically interacted with RNA binding proteins, particularly members of the serine/arginine-rich (SR) family of splicing factors. Clk/Sty itself has an serine/arginine-rich non-catalytic N-terminal region which is important for its association with SR splicing factors. In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Tryptic phosphopeptide mapping demonstrated that the sites on ASF/SF2 phosphorylated in vitro overlap with those phosphorylated in vivo. Immunofluorescence studies showed that a catalytically inactive form of Clk/Sty co-localized with SR proteins in nuclear speckles. Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors.

Amino Acid Sequence↗
PubMed1996

Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase.

The interaction of cells with the extracellular matrix regulates cell shape, motility, growth, survival, differentiation and gene expression, through integrin-mediated signal transduction. We used a two-hybrid screen to isolate genes encoding proteins that interact with the beta 1-integrin cytoplasmic domain. The most frequently isolated complementary DNA encoded a new, 59K serine/threonine protein kinase, containing four ankyrin-like repeats. We report here that this integrin-linked kinase (ILK) phosphorylated a beta 1-integrin cytoplasmic domain peptide in vitro and coimmunoprecipitated with beta 1 in lysates of mammalian cells. Endogenous ILK kinase activity was reduced in response to fibronectin. Overexpression of p59ILK disrupted epithelial cell architecture and inhibited adhesion to integrin substrates, while inducing anchorage-independent growth. We propose that ILK is a receptor-proximal protein kinase regulating integrin-mediated signal transduction.

Amino Acid Sequence↗
PubMed1996

Legionellosis linked with a hotel car park--how many were infected?

An outbreak of legionellosis associated with a hotel in Sydney, Australia, and the subsequent epidemiological and environmental investigations are described. Four cases of Legionnaires' disease were notified to the Public Health Unit. A cross-sectional study of 184 people who attended a seminar at the hotel was carried out. Serological and questionnaire data were obtained for 152 (83%) of these. Twenty-eight (18%) respondents reported symptoms compatible with legionellosis. Thirty-three subjects (22%) had indirect fluorescent antibody (IFA) titres to Legionella pneumophila serogroup 1 (Lp-1) of 128 or higher. The only site which those with symptoms of legionellosis and IFA titre > or = 128 were more likely to have visited than controls was the hotel car park (adjusted odds ratio [OR] 14.7, 95% confidence interval [CI]: 1.8-123.1). Those with symptoms compatible with legionellosis, but whose IFA titres were < 128 were also more likely to have visited the hotel car park (adjusted OR 4.4, 95% CI: 1.5-12.9). Seroprevalence of Lp-1 antibodies was higher in those who attended the seminar than in a population sample of similar age. Findings suggested that the 4 cases represented a small fraction of all those infected, and highlighted difficulties in defining illness caused by Lp-1 and in interpreting serology.

Adult↗
PubMed1995

Changes in cancer incidence and mortality in New South Wales.

OBJECTIVE: To assess changes in cancer incidence and mortality in New South Wales (NSW) between 1973-1977 and 1988-1992. DESIGN: Descriptive analysis of statutory cancer notifications to the NSW Central Cancer Registry. OUTCOME MEASURES: Age-standardised incidence and mortality rates calculated with the "world" standard population. RESULTS: Overall cancer incidence rose markedly, from 251 to 318 per 100,000 in men and from 202 to 241 per 100,000 in women. The rise was greatest in the 60-and-over age group. Cancer mortality fell marginally in men (from 166 to 162 per 100,000) and did not change in women (100 per 100,000 in both periods). It fell in the under-60 age group, and remained stable or rose in older people. Prostate and breast cancers and melanoma of the skin accounted for about half the increase in incidence. Both incidence and mortality increased significantly (P < 0.01) for melanoma and non-Hodgkin's lymphomas in men and lung cancer in women, and fell substantially for stomach cancer in both sexes, lung cancer in men and cervical cancer in women. Despite increasing incidence, mortality, also fell for testicular cancer in men and rectal cancer in women and for leukaemias in children. CONCLUSIONS: The major factor causing the increased incidence of overall cancer was earlier detection. Altered exposure to risk factors could be identified for only a minority of the changes.

Adolescent↗
PubMed1995

Alternative splicing of STY, a nuclear dual specificity kinase.

The LAMMER subfamily of kinases has been conserved throughout evolution, and its members are thought to play important roles in the regulation of cellular growth and differentiation programs. STY is a murine LAMMER kinase which has been implicated in the control of PC12 cell differentiation. Multiple transcripts are derived from the Sty gene, and their relative abundance is developmentally regulated. Alternative splicing of the primary Sty transcript generates mRNAs encoding full-length catalytically active (STY) and truncated, kinase-deficient polypeptides. Both STY and its truncated isoform, STYT, are localized in the nucleus and are capable of heterodimerizing. We also demonstrate that STY functions as a dual specificity kinase in mammalian cells.

Alternative Splicing↗
PubMed1994

Identification of tyrosine 620 as the major phosphorylation site of myelin-associated glycoprotein and its implication in interacting with signaling molecules.

Myelin-associated glycoprotein (MAG) is a myelin-specific cell adhesion molecule of the immunoglobulin supergene family and is tyrosine-phosphorylated in the developing brain. To define the role of MAG in signal transduction, the tyrosine phosphorylation sites were analyzed. The major tyrosine phosphorylation residue was identified as Tyr-620, which was found to interact specifically with the SH2 domains of phospholipase C (PLC gamma). This domain may represent a novel protein binding motif that can be regulated by tyrosine phosphorylation. MAG also specifically bound the Fyn tyrosine kinase, suggesting that MAG serves as a docking protein that allows the interaction between different signaling molecules.

Animals↗
PubMed1994

Dual specificity kinases--a new family of signal transducers.

Phosphorylation/dephosphorylation reactions are one of the dynamic mechanisms through which cells modulate protein activity in response to environmental stimuli. The eukaryotic molecules which are responsible for the phosphorylation of serine, threonine and tyrosine residues appear to have co-ordinately evolved from simple prokaryotic enzymes which primarily respond to nutritional cues. In multicellular eukaryotes the complexity of data transfer greatly exceeds that of simple bacteria. The eukaryotic cell needs to exchange information with neighbouring and distant sister cells. Positional, nutritional and hormonal data are transmitted from the extracellular milieu across the plasma membrane and into the cytoplasm. In certain cases the signal must pass into the nucleus or other subcellular organelles where it is decoded and the proper cellular response initiated. All of these events have been shown to have a protein kinase component and it seems likely that in mammalian cells over 1,000 different kinase molecules have evolved to form the requisite signal transducing networks. In this review we describe a previously unappreciated family of protein kinases, the dual specificity or DSK kinases, which play important roles in the regulation of normal cellular growth and differentiation.

Animals↗
PubMed1994

An evaluation of five different methods for estimating proliferation in human colorectal adenocarcinomas.

Five different methods of determining cell proliferation have been compared in samples taken from a group of 125 human colorectal tumours labelled in vivo with iododeoxy-uridine (IUdR). The labelling index (LI) was obtained immunocytochemically using monoclonal antibodies against proliferating cell nuclear antigen (PCNA), the Ki67 antigen and IUdR (IUdRimm). Incorporation of IUdR was also determined flow cytometrically (IUdRfcm) and PCNA expression was measured in both formalin- and methanol-fixed tissue (PCNAf and PCNAm respectively). There was significant variation in the results obtained both within and between the different assays. Paired analysis of the data showed that the correlation between the different methods of determining the LI was poor. However, the IUdRfcm LI was significantly correlated with both IUdRimm (r = 0.39; n = 78; P < 0.001 by Spearman's test) and Ki67 LIs (r = 0.32; n = 87; P < 0.001). The IUdRimm LI was also significantly related to the Ki67 LI (r = 0.44; n = 60; P < 0.001). The median IUdRfcm and IUdRimm LIs were significantly higher in the aneuploid vs. the diploid tumours (17.4% vs. 6.2% for IUdRfcm; 23.2% vs. 18.9 for the IUdRimm; P < 0.001 and P = 0.014 respectively by Mann-Whitney U-test) but none of the other proliferative indices showed this relationship. Finally, none of the LIs showed a significant association with the clinical characteristics of the tumours such as stage, grade, age, sex or fixity. The findings of this investigation highlight the need for carefully controlled studies when assessing the value of proliferation markers in solid human tumours.

Adenocarcinoma↗
PubMed1994

Seroprevalence of hepatitis A antibodies among residents of a centre for people with developmental disabilities.

BACKGROUND: In February 1993, 11 cases of hepatitis A virus (HAV) were identified in permanent residents of a centre for young people with developmental disabilities. AIMS: To define the extent of the outbreak in the centre, to determine the seroprevalence of hepatitis A antibodies (anti-HAV) in permanent residents, and to ascertain risk factors for serological evidence of HAV infection. METHODS: A cross-sectional serological survey of 270 permanent residents, aged eight to 40 years, in a centre for people with developmental disabilities, was conducted in western Sydney. Using a radioimmunoassay technique, sera were tested for anti-HAV (IgM and total antibody). We used logistic regression to determine risk factors for presence of anti-HAV. RESULTS: Blood samples were collected from 259 permanent residents (96%). Serological testing revealed anti-HAV in 128 residents tested (49%). Presence of anti-HAV was associated with living in specific residential units, and with residents' age and length of stay at the centre, but was not associated with reported behavioural factors. CONCLUSIONS: More than half of the residents of the centre were susceptible to HAV infection. Behavioural characteristics of the residents and their close contact with each other make HAV transmission difficult to control. HAV vaccine should be promoted in communities at risk, such as those with developmental disabilities.

Adolescent↗
PubMed1993

Phosphorylation and disruption of intermediate filament proteins in oligodendrocyte precursor cultures treated with calyculin A.

Treatment of primary cultures of oligodendrocyte precursors with calyculin A, a potent inhibitor of protein phosphatases 1 and 2A, caused the phosphorylation of two intermediate filament components, nestin and vimentin. Phosphoamino acid analysis demonstrated that phosphorylation took place mainly on serine and to a lesser extent on threonine residues. In addition, calyculin A treatment caused a shift in the distribution of the two proteins from the Triton-X-100 insoluble fraction to the detergent soluble fraction as demonstrated by immunoblotting. This redistribution, which was evident within 15 min after treatment and was nearly completed by 90 min, was accompanied by a disruption of the intermediate filament network. Thus, both nestin and vimentin retracted from the cytoplasmic processes to form a large perikaryal ring as shown by immunocytochemical analysis. Both morphological and biochemical changes were reversed 2-5 hr after removal of calyculin A from the culture medium.

Amino Acids↗
PubMed1993

The epidemiology of incomplete childhood immunization: an analysis of reported immunization status in outer western Sydney.

We surveyed parents of children enrolled in kindergarten in 1992 in outer western Sydney and the Blue Mountains. Using parents' reports, we determined the prevalence of immunization uptake for children starting school, compared the prevalence of immunization uptake among Catholic, government and independent schools, and identified immunization providers. We also documented parental beliefs about immunization and their influence on immunization status, and identified risk factors for incomplete immunization. Nearly 89% of children were reported to be fully immunized. Immunization status did not vary significantly among the different types of school. General practitioners provided 84% of all immunizations and local councils 11%. Incomplete immunization was associated with more negative beliefs in immunization, with post-secondary education and with families who do not speak English at home. Reminder letters had little effect on immunization status.

Attitude to Health↗