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Biomedical subjects

F Fee

Publications and source records attributed to F Fee.

13 recordsLinked to original sources
PubMed1999

Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP.

Raf-1 phosphorylates and activates MEK-1, a kinase that activates the extracellular signal regulated kinases (ERK). This kinase cascade controls the proliferation and differentiation of different cell types. Here we describe a Raf-1-interacting protein, isolated using a yeast two-hybrid screen. This protein inhibits the phosphorylation and activation of MEK by Raf-1 and is designated RKIP (Raf kinase inhibitor protein). In vitro, RKIP binds to Raf-1, MEK and ERK, but not to Ras. RKIP co-immunoprecipitates with Raf-1 and MEK from cell lysates and colocalizes with Raf-1 when examined by confocal microscopy. RKIP is not a substrate for Raf-1 or MEK, but competitively disrupts the interaction between these kinases. RKIP overexpression interferes with the activation of MEK and ERK, induction of AP-1-dependent reporter genes and transformation elicited by an oncogenically activated Raf-1 kinase. Downregulation of endogenous RKIP by expression of antisense RNA or antibody microinjection induces the activation of MEK-, ERK- and AP-1-dependent transcription. RKIP represents a new class of protein-kinase-inhibitor protein that regulates the activity of the Raf/MEK/ERK module.

3T3 Cells↗
PubMed1997

Fragile X, iron, and neurodevelopmental screening in 8 year old children with mild to moderate learning difficulties.

OBJECTIVE: To examine the value of neurodevelopmental examination, fragile X testing, iron studies, and other screening procedures in children with mild to moderate learning difficulties. DESIGN: A cross sectional case-control study. SUBJECTS: A 34% random sample (n = 130) of children with mild to moderate learning difficulties born between 01/07/83 and 30/06/84 and resident in North and West Belfast. Controls were 130 children without learning difficulties matched for age and geographical area. RESULTS: The prevalence of mild to moderate learning difficulties in North and West Belfast was 16%; 115 (89%) of the learning difficulties group and 80 (58%) of the control group consented to participate. Children in the learning difficulties group scored significantly lower in neurodevelopmental testing and were more likely to fail their audiometry assessment than controls. Children in the learning difficulties group were also more likely to be anaemic and had lower serum iron and transferrin saturation than controls. No cases of fragile X were identified. Thyroid function tests and urinary amino acids were all within normal limits There were no significant differences in anthropometry, head circumference, or formal neurological examinations. CONCLUSIONS: Children with learning difficulties are more likely to be neurodevelopmentally immature and iron depleted than controls. Iron depletion should be aggressively sought and treated. The role for routine assessment for fragile X, thyroid function tests, and amino acid chromatography is doubtful.

Amino Acids↗
PubMed1997

Profiles of cognitive functioning in chronic spinal cord injury and the role of moderating variables.

A traumatic spinal cord injury (SCI) is accompanied by a documented moderate to severe head injury in significant numbers of SCI patients. In a previous study (Dowler et al., 1995), cognitive deficits were found in 41% of the SCI individuals who were studied with a chronic injury from a traumatic event. The present study investigated whether clinically useful subtypes of normal and impaired cognition could be identified in a chronic (M = 17 years postinjury) SCI sample using a cluster analysis of neuropsychological test performance. A battery of 16 neuropsychological tests was administered to 91 SCI patients and 75 control participants. Composite scores, reflecting performance in different cognitive domains, were derived from a factor analysis of the battery, and these scores were then used in the cluster analysis. A six-cluster solution generated the most distinct and clinically relevant SCI group profiles. Two of the cognitive profiles were characterized by normal functioning in all cognitive domains, but they were distinguished by differences in performance levels. The remaining four SCI groups (60% of the sample) showed clinically significant deficits in one or more cognitive domains, with different groups showing moderate attention and processing speed deficits, mild deficits in processing speed, executive processing difficulties, or moderate memory impairments. Though age and premorbid intellectual ability were strong predictors of the cognitive profiles of some SCI groups, when these factors were controlled, the findings suggested that the patterns of cognitive impairment were likely due to a potential concomitant head injury.

Adult↗
PubMed1996

Multigenic control of skin tumour development in mice.

Different inbred mouse strains vary greatly in their susceptibility to tumour development in a variety of tissues. Intraspecific and interspecific crosses can, therefore, be used to map the loci that control this predisposition. Crosses of Mus musculus with Mus spretus are highly resistant to tumour development in the skin, liver, lung and lymphoid system. M. spretus, therefore, has dominantly acting resistance loci, which we have attempted to map. More than 350 interspecific backcross mice were followed for 18 months to assess susceptibility to development of chemically induced papillomas and carcinomas. The results were analysed using a combination of MAPMAKER/QTL analysis and multiple regression analysis for the determination of linkage in multigenic quantitative traits. The results showed clearly that at least three genes on chromosomes 5 and 7 control resistance to tumour development. Importantly, some genes confer resistance to benign tumours but they have relatively little effect on malignant progression. This suggests the existence of different classes of benign tumours: those that are capable of tumour progression and those that have only a very low probability of becoming malignant. Identification of these genes will improve our understanding of mechanisms of carcinogenesis and may provide a novel route to the identification of "low-penetrance' human tumour susceptibility genes.

Animals↗
PubMed1996

Predictive value of preschool surveillance in detecting learning difficulties.

OBJECTIVES: The Hall report specified the early detection of mild to moderate learning difficulties as one aim of child health surveillance (CHS). This study examines the efficacy of preschool CHS in the early recognition of children with these disorders. DESIGN: A retrospective case-control study. SUBJECTS: All children (n = 408) with mild to moderate learning difficulties born between 1 July 1983 and 30 June 1984 and resident in North and West Belfast. CONTROLS: 2406 birth records and 150 full child health records controlled for age and geographical area. RESULTS: The prevalence of mild to moderate learning difficulties in North and West Belfast was 16%. Only 6% of children with learning difficulties were identified by the CHS in the preschool period, although the detection rate for children eventually requiring placement in schools for moderate learning difficulties was better. Coverage of the CHS ranged from 90% at the 2 year examination to 98% at the 4 year examination. Perinatal variables associated with learning difficulties after multiple logistic regression analysis were lower social class (odds ratio (OR) 3.9), prematurity < 35 weeks (OR 3.0), male sex (OR 1.6), and birth to an unmarried mother (OR 0.6). Independent preschool variables identified by the CHS were speech delay (OR 3.3), poor parenting skills (OR 4.0), behaviour problems (OR 2.8), enuresis (OR 2.4), poor visual acuity (OR 1.8), and otitis media with effusion (OR 1.4). A statistical model for the early detection of learning difficulties using these risk factors is unable to predict accurately the children who will develop mild to moderate learning difficulties. CONCLUSIONS: The CHS as it existed from 1983 to 1989 in North and West Belfast was poorly sensitive to the detection of mild to moderate learning difficulties despite excellent coverage. An accurate predictive model for learning difficulties could not be developed from the risk factors documented by the CHS.

Case-Control Studies↗
PubMed1995

Distinct genetic loci control development of benign and malignant skin tumours in mice.

Genetic susceptibility to chemically induced skin cancer in mice is controlled by multiple unlinked genetic loci. Mus spretus mice have dominant resistance genes which confer resistance to interspecific F1 hybrids with susceptible Mus musculus strains. We have mapped three major resistance loci using a combination of Mapmaker/QTL analysis and multiple regression analysis to mouse chromosomes 5 and 7. At least two independent loci on chromosome 7 exert their effects primarily during benign tumour development and have very little influence on tumour progression. On the other hand, probably a single locus on chromosome 5 affects both early and late stages of malignancy. The results indicate that benign and malignant tumours are largely under independent genetic control.

Animals↗
PubMed1993

Allelotype analysis of mouse skin tumors using polymorphic microsatellites: sequential genetic alterations on chromosomes 6, 7, and 11.

Allelotype analysis of human tumors has been instrumental in the effort to discover and clone novel tumor suppressor genes. However, this approach has not been systematically applied to animal models of carcinogenesis. We describe here the first attempt to allelotype a nonhuman tumor, i.e., chemically induced mouse skin tumors, using a panel of polymorphic microsatellite markers. The results indicated that markers on chromosomes 6 and 7 were imbalanced, consistent with trisomy in both benign and malignant skin tumors. A proportion of carcinomas also showed loss of heterozygosity on chromosome 11, where the p53 gene is located, and more rarely, on chromosomes 4, 6, and 15. The significance of these alterations is highlighted by the observations of no allelic imbalance for markers on 12 other chromosomes.

Alleles↗
PubMed1991

Structural analysis of the mouse c-Ha-ras gene promoter.

Previous studies have demonstrated that the mouse c-Harvey ras proto-oncogene (c-Ha-ras) promoter sequences are GC rich and contain several potential transcription factor SP1 binding sites. We investigated the endonuclease hypersensitivity of this region in nuclei in vitro and whole mouse tissues in vivo and identified a very strong, ubiquitous hypersensitive site covering the proximal promoter sequences. Footprint protection studies using nuclear extracts from various cell types including fibroblasts, erythroid cells, and both normal and transformed epithelial cells revealed a consistent protein-binding pattern. Five protein binding sites were observed, four of which correlated with potential SP1 binding sites. Competition experiments using an oligonucleotide corresponding to a consensus SP1 binding site confirmed that these sequences were indeed bound by the SP1 (or SP1-like) trans-acting factor. In addition, no differences were observed between the footprint patterns obtained using extracts from cells of different lineages or between normal and transformed epithelial cells carrying activated ras genes. The controlling elements responsible for differential c-Ha-ras transcription between cell types or at different stages of carcinogenesis therefore probably lie in other regions of the gene.

Animals↗
PubMed1989

Chemical induction of oncogene mutations and growth factor activity in mouse skin carcinogenesis.

The goal of understanding the molecular basis of human tumor development has been greatly facilitated by the use of animal model systems in which the etiology of tumor development can be carefully controlled. Environmental chemicals, either naturally occurring or artificially produced, are thought to make a major contribution to the human tumor burden. Many of the concepts of multistage carcinogenesis have been developed and refined using the mouse skin model system and the work described in this article has been carried out in an attempt to analyze the molecular changes that are associated with the initiation of tumor development, the selection of initiated cells to form papillomas, or the progression of premalignant tumors to carcinoma. We have analyzed a number of skin tumors induced in mice by a two-stage initiation and promotion protocol and have detected a high frequency of c-ras oncogene mutations in this system. The mutation found in each case correlates well with the known reactivity of the carcinogens used. It has also been shown that where ras activation occurs this represents an early event in the tumor model system. Transforming growth factor beta is induced in mouse skin by tumor promoter treatment and may therefore play a role in the selection of initiated cells to form papillomas. Additional events, some of which involve the loss of normal ras alleles and possibly tumor suppressor genes, appear to take place at a later stage of carcinogenesis.

Animals↗
PubMed1988

Localized production of TGF-beta mRNA in tumour promoter-stimulated mouse epidermis.

Tumour promoters induce a wide spectrum of morphological and biochemical alterations when applied to mouse epidermis in vivo. These include the induction of RNA, DNA and protein synthesis during discrete phases of proliferation and differentiation. This constitutes an ideal model for studying molecular events underlying the disruption of epidermal homeostasis by TPA, and its subsequent re-establishment. Transforming growth factor-beta (TGF-beta) can induce either growth stimulation, inhibition, or differentiation, depending on the target cell. A function has been proposed for TGF-beta in wound healing and in tumour promotion, but the main source of TGF-beta is generally thought to be platelets, macrophages or lymphocytes, and a direct role for this growth factor in regulating tissue homeostasis in vivo has not been demonstrated. We show here that when the tumour promoter 12-tetradecanoyl-phorbol-13-acetate (TPA) is applied to the skin of mice, very high levels of TGF-beta messenger RNA are induced in the epidermal cells. In situ hybridization techniques show that the main site of TGF-beta synthesis is in the suprabasal differentiating epidermal cells. These results suggest that TGF-beta may be a natural regulator of epidermal homeostasis which is important in tumour promotion.

Animals↗
PubMed1988

Isolation and characterization of the 5' flanking region of the mouse c-Harvey-ras gene.

The complete 5' flanking region of the murine c-Ha-ras gene was cloned and sequenced. An untranslated exon (-1) was identified and the promoter region of the gene located. Like the rat and human homologues, the murine promoter is GC rich and contains several GC boxes together with a CAAT element, but lacks a TATA box, an arrangement similar to that found in many housekeeping genes. From primer extension studies, the gene was shown to have three transcriptional start sites, whose positions differ from those previously found for the human gene. No alterations in these start sites were detected between the normal gene and activated Ha-ras genes from mouse skin tumors. A region of strong homology between mouse, rat, and human Ha-ras genes exists within the large intron separating exon (-1) from the first coding exon. In addition, from chloramphenicol acetyltransferase assays, the upstream region has promoter activity which appears to be enhanced by the inclusion of sequences within this intron.

Animals↗