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A Ashworth

Publications and source records attributed to A Ashworth.

At least 55 records · Page 3Linked to original sources
PubMed1999

The pathology of familial breast cancer: How do the functions of BRCA1 and BRCA2 relate to breast tumour pathology?

Women with mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, have an increased risk of developing breast cancer. Both BRCA1 and BRCA2 are thought to be tumour suppressor genes since the wild type alleles of these genes are lost in tumours from heterozygous carriers. Several functions have been proposed for the proteins encoded by these genes which could explain their roles in tumour suppression. Both BRCA1 and BRCA2 have been suggested to have a role in transcriptional regulation and several potential BRCA1 target genes have been identified. The nature of these genes suggests that loss of BRCA1 could lead to inappropriate proliferation, consistent with the high mitotic grade of BRCA1-associated tumours. BRCA1 and BRCA2 have also been implicated in DNA repair and regulation of centrosome number. Loss of either of these functions would be expected to lead to chromosomal instability, which is observed in BRCA1 and BRCA2-associated tumours. Taken together, these studies give an insight into the pathogenesis of BRCA-associated tumours and will inform future therapeutic strategies.

BRCA1 Protein↗
PubMed1999

Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification.

Women heterozygous for mutations in the breast-cancer susceptibility genes BRCA1 and BRCA2 have a highly elevated risk of developing breast cancer [1]. BRCA1 and BRCA2 encode large proteins with no sequence similarity to one another. Although involvement in DNA repair and transcription has been suggested, it is still not understood how loss of function of these genes leads to breast cancer [2]. Embryonic fibroblasts (MEFs) derived from mice homozygous for a hypomorphic mutation (Brca2(Tr2014)) within the 3' region of exon 11 in Brca2 [3], or a similar mutation (Brca2(Tr)) [4], proliferate poorly in culture and overexpress the tumour suppressor p53 and the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). These MEFs have intact p53-dependent DNA damage G(1)-S [3] [4] and G(2)-M checkpoints [4], but are impaired in DNA double-strand break repair [3] and develop chromosome aberrations [4]. Here, we report that Brca2(Tr2014/Tr2014) MEFs frequently develop micronuclei. These abnormal DNA-containing bodies were formed through both loss of acentric chromosome fragments and by chromosome missegregation, which resulted in aneuploidy. Absence of Brca2 also led to centrosome amplification, which we found associated with the formation of micronuclei. These data suggest a potential mechanism whereby loss of BRCA2 may, within subclones, drive the loss of cell-cycle regulation genes, enabling proliferation and tumourigenesis.

Aneuploidy↗
PubMed1999

Evolutionary rate of a gene affected by chromosomal position.

Genes evolve at different rates depending on the strength of selective pressure to maintain their function. Chromosomal position can also have an influence [1] [2]. The pseudoautosomal region (PAR) of mammalian sex chromosomes is a small region of sequence identity that is the site of an obligatory pairing and recombination event between the X and Y chromosomes during male meiosis [3] [4] [5] [6]. During female meiosis, X chromosomes can pair and recombine along their entire length. Recombination in the PAR is therefore approximately 10 times greater in male meiosis compared with female meiosis [4] [5] [6]. The gene Fxy (also known as MID1 [7]) spans the pseudoautosomal boundary (PAB) in the laboratory mouse (Mus musculus domesticus, C57BL/6) such that the 5' three exons of the gene are located on the X chromosome but the seven exons encoding the carboxy-terminal two-thirds of the protein are located within the PAR and are therefore present on both the X and Y chromosomes [8]. In humans [7] [9], the rat, and the wild mouse species Mus spretus, the gene is entirely X-unique. Here, we report that the rate of sequence divergence of the 3' end of the Fxy gene is much higher (estimated at 170-fold higher for synonymous sites) when pseudoautosomal (present on both the X and Y chromosomes) than when X-unique. Thus, chromosomal position can directly affect the rate of evolution of a gene. This finding also provides support for the suggestion that regions of the genome with a high recombination frequency, such as the PAR, may have an intrinsically elevated rate of sequence divergence.

Animals↗
PubMed1999

JNK activation is not required for Fas-mediated apoptosis.

Fas ligation in the presence of cycloheximide induced Jun N-terminal kinase 1 (JNK1) and JNK2 phosphorylation, caspase activation and cell death in the IL-3-dependent cell line BAF3. Fas-mediated apoptosis was prevented by expression of dominant negative FADD but not inhibited by IL-3. To investigate the role of JNK activation in this process, we examined cells over-expressing a JNK-specific phosphatase M3/6. M3/6 prevented Fas stimulation of JNK, but did not affect Fas-mediated caspase activation or cell death, demonstrating that JNK activation is not required for these processes.

Animals↗
PubMed1999

sox30: a novel zebrafish sox gene expressed in a restricted manner at the midbrain-hindbrain boundary during neurogenesis.

The Sox family of proteins is thought to act to regulate gene expression in a wide variety of developmental processes. Here we describe the cloning of sox30, a novel sox gene from the zebrafish (Danio rerio). In situ hybridization shows that sox30 is expressed in a restricted manner at the boundary between the midbrain and hindbrain during nervous system development. This expression pattern is in direct contrast to that of most other neuronally expressed Sox genes which are expressed throughout the nervous system.

Amino Acid Sequence↗
PubMed1999

Effect of breastfeeding and morbidity on the development of low birthweight term babies in Brazil.

Low birthweight (LBW) occurs in 17% of births in developing countries and many of them are full term. The subsequent development of LBW term infants is poorer than higher birthweight children and more likely to be affected by poor social circumstances. We investigated the effects of morbidity and breastfeeding on the development of these LBW term infants. Two parallel cohorts (n = 131 + 131) of LBW term (1500-2499 g) and higher birthweight (3000-3499 g) infants were recruited from six maternity centers in northeast Brazil. The longitudinal prevalence of morbidity and the frequency of breastfeeding over the first 6 mo of life were assessed. The infants' development was assessed on the Bayley Scales at 6 and 12 mo, and we previously reported that the low birthweight group had lower scores than the higher birthweight group. Hospitalizations in the first 6 mo were negatively associated with 6-mo and 12-mo Bayley scores in both groups. Among LBW infants, but not higher birthweight infants, there were significant associations between the prevalence of diarrhea and mental and motor development at 6 mo and mental development at 12 mo. Breastfeeding frequency in the first 4 wk of life was positively associated with mental development in both birthweight groups at 6 mo but not at 12 mo. Breastfeeding beyond 4 wk was not associated with the children's development. We conclude that low birthweight infants are especially vulnerable to the effects of diarrhea, and the greater frequency and differential effect of diarrhea partly explains their poorer development.

Birth Weight↗
PubMed1999

Potential interventions for the prevention of childhood pneumonia in developing countries: improving nutrition.

Acute respiratory infections are the leading cause of childhood death in developing countries. Current efforts at mortality control focus on case management and immunization, but other preventive strategies may have a broader and more sustainable effect. This review, commissioned by the World Health Organization, examines the relations between pneumonia and nutritional factors and estimates the potential effect of nutritional interventions. Low birth weight, malnutrition (as assessed through anthropometry), and lack of breast-feeding appear to be important risk factors for childhood pneumonia, and nutritional interventions may have a sizeable effect in reducing deaths from pneumonia. For all regions except Latin America, interventions to prevent malnutrition and low birth weight look more promising than does breast-feeding promotion. In Latin America, breast-feeding promotion would have an effect similar to that of improving birth weights, whereas interventions to prevent malnutrition are likely to have less of an effect. These findings emphasize the need for tailoring interventions to specific national and even local conditions.

Breast Feeding↗
PubMed1999

The mouse Peutz-Jeghers syndrome gene Lkb1 encodes a nuclear protein kinase.

The protein kinase gene LKB1 has recently been identified as the gene mutated in the Peutz-Jeghers cancer predisposition syndrome. This condition is characterized by inherited susceptibility to a range of cancers but in particular those of the gastrointestinal tract. Here we have characterized the mouse Lkb1 gene. The mouse Lkb1 gene consists of 10 exons covering approximately 15 kb in length, maps to mouse chromosome 10 and encodes a protein showing strong sequence similarity to human LKB1. The 3" end of Lkb1 in the mouse is in very close proximity to the 3" end of an apparently unrelated gene R29144/1 and it seems probable that overlapping transcripts of the two genes are produced. Using transfection of Lkb1 cDNAs we have shown that Lkb1 is most likely a nuclear protein and have defined a nuclear localization signal within the protein sequence. Thus the defect in Peutz-Jeghers syndrome may directly result in changes in gene expression in the nucleus of target cells.

AMP-Activated Protein Kinases↗
PubMed1999

Influence of heavy agricultural work during pregnancy on birthweight in northeast Brazil.

BACKGROUND: Women in developing countries often continue their agricultural work during late pregnancy. Whether this adversely affects birthweight is not clear from previous studies as few controlled for confounding factors. This study seeks to clarify this issue. METHODS: This retrospective cohort study investigated 958 low-income women and their singleton newborn babies residing in a region of Northeast Brazil dependent on sugar-cane production. Women were recruited at maternity centres, when attending for delivery, and were allocated to one of two groups according to their exposure to heavy agricultural labour for at least 3 months during the second and third trimesters of pregnancy (n = 250), or to household activities only (n = 708). RESULTS: The mean birthweight of infants born to women who worked in agriculture during 9 months of pregnancy was 190 g lower than that of the non-exposed group (P = 0.02). After controlling for confounding factors, the adjusted effect was 117 g (P = 0.05). Heavy agricultural work for 6, 7 or 8 months had no significant effect. CONCLUSIONS: These findings suggest that working throughout pregnancy significantly reduces birthweight in this low-income population.

Adolescent↗
PubMed1999

Are breastfeeding promotion messages influencing mothers in Bangladesh? Results from an urban survey in Dhaka, Bangladesh.

Despite the launching of a national breastfeeding promotion campaign in Bangladesh in 1989, exclusive breastfeeding rates remain low. To understand mothers' perceptions of the campaign messages and the reasons for current practices, a random sample of 1100 lower middle class mothers in Dhaka, with infants aged 0-6 months, were interviewed in 1995. Although 99 per cent of mothers fed colostrum within 3 days of delivery, 92 per cent also gave one or more traditional prelacteals, and 68 per cent gave postlacteals. This could be due to ambiguity of the message, which simply advocated giving colostrum without indicating its exclusive use, thereby appearing compatible with traditional perceptions that colostrum alone is insufficient. Ninety-nine per cent of mothers reported hearing the breastfeeding messages or receiving advice, and 97 per cent stated that they understood the meaning of exclusive breastfeeding. But this concept was not correctly understood, as many thought it meant feeding breastmilk and water. The prevalence of exclusive breastfeeding was 15 per cent, and complementary foods were introduced early (median 30 days). Many mothers doubted the message that breastmilk alone is sufficient for 5 months. Messages to promote improved breastfeeding practices in Bangladesh need to be revised to clear misconceptions.

Adult↗
PubMed1999

Interaction between the product of the breast cancer susceptibility gene BRCA2 and DSS1, a protein functionally conserved from yeast to mammals.

Germ line mutations in the breast cancer susceptibility gene BRCA2 predispose to early-onset breast cancer, but the function of the nuclear protein encoded by the gene is ill defined. Using the yeast two-hybrid system with fragments of human BRCA2, we identified an interaction with the human DSS1 (deleted in split hand/split foot) gene. Yeast and mammalian two-hybrid assays showed that DSS1 can associate with BRCA2 in the region of amino acids 2472 to 2957 in the C terminus of the protein. Using coimmunoprecipitation of epitope-tagged BRCA2 and DSS1 cDNA constructs transiently expressed in COS cells, we were able to demonstrate an association. Furthermore, endogenous BRCA2 could be coimmunoprecipitated with endogenous DSS1 in MCF7 cells, demonstrating an in vivo association. Apparent orthologues of the mammalian DSS1 gene were identified in the genome of the yeasts Schizosaccharomyces pombe and Saccharomyces cerevisiae. Yeast strains in which these DSS1-like genes were deleted showed a temperature-sensitive growth phenotype, which was analyzed by flow cytometry. This provides evidence for a link between the BRCA2 tumor suppressor gene and a gene required for completion of the cell cycle.

Amino Acid Sequence↗
PubMed1999

Molecular genetic characterisation of frontotemporal dementia on chromosome 3.

We have previously localized a locus causing familial nonspecific dementia to the centromeric region of chromosome 3 in a pedigree from the Jutland area of Denmark. This pedigree shows anticipation. Here we present further analysis of these anticipation data which are suggestive of trinucleotide repeat expansion involvement. We also outline our strategies to clone the mutant gene via its putative associated trinucleotide repeat sequence.

Adult↗
PubMed1998

Patchy fur, a mouse coat mutation associated with X-Y nondisjunction, maps to the pseudoautosomal boundary region.

Patchy fur is a semidominant X-linked mutation in the mouse, resulting in a sparse coat. The Paf mutation also alters the normal segregation of the X and the Y chromosomes during male meiosis by causing nondisjunction at anaphase I. Analysis of 1139 female meioses from an intersubspecific backcross using 15 PCR-based markers localizes Paf to an approximately 0.2-cM interval that includes the pseudoautosomal boundary. The meiotic nondisjunction phenotype may result from a chromosomal rearrangement that includes pseudoautosomal sequences and affects XY pairing.

Animals↗
PubMed1998

Structure and chromosomal mapping of the TNF-alpha inducible endothelial protein 1 (Edp1) gene in the mouse.

EDP1 was identified as a human gene activated transcriptionally by tumour necrosis factor alpha in endothelial cells. Here we have characterised the mouse Edp1 gene. We show that the gene encodes a highly conserved protein and describe its intron/exon structure. The presence of related genes in the sequence databases suggests that Edp1 is part of a gene family. Fine mapping of the gene in the mouse genome indicates that, as expected from its location on human chromosome 17, the mouse Edp1 gene maps to mouse chromosome 11. However, surprisingly, the gene does not map to the expected region of mouse chromosome 11 suggesting that a change in the order of genes has occurred within a conserved linkage group.

Adaptor Proteins, Signal Transducing↗
PubMed1998

The mitogen-activated protein kinase phosphatase-3 N-terminal noncatalytic region is responsible for tight substrate binding and enzymatic specificity.

We have reported recently that the dual specificity mitogen-activated protein kinase phosphatase-3 (MKP-3) elicits highly selective inactivation of the extracellular signal-regulated kinase (ERK) class of mitogen-activated protein (MAP) kinases (Muda, M., Theodosiou, A., Rodrigues, N., Boschert, U., Camps, M., Gillieron, C., Davies, K., Ashworth, A., and Arkinstall, S. (1996) J. Biol. Chem. 271, 27205-27208). We now show that MKP-3 enzymatic specificity is paralleled by tight binding to both ERK1 and ERK2 while, in contrast, little or no interaction with either c-Jun N-terminal kinase/stress activated protein kinase (JNK/SAPK) or p38 MAP kinases was detected. Further study revealed that the N-terminal noncatalytic domain of MKP-3 (MKP-3DeltaC) binds both ERK1 and ERK2, while the C-terminal MKP-3 catalytic core (MKP-3DeltaN) fails to precipitate either of these MAP kinases. A chimera consisting of the N-terminal half of MKP-3 with the C-terminal catalytic core of M3-6 also bound tightly to ERK1 but not to JNK3/SAPKbeta. Consistent with a role for N-terminal binding in determining MKP-3 specificity, at least 10-fold higher concentrations of purified MKP-3DeltaN than full-length MKP-3 is required to inhibit ERK2 activity. In contrast, both MKP-3DeltaN and full-length MKP-3 inactivate JNK/SAPK and p38 MAP kinases at similarly high concentrations. Also, a chimera of the M3-6 N terminus with the MKP-3 catalytic core which fails to bind ERK elicits non selective inactivation of ERK1 and JNK3/SAPKbeta. Together, these observations suggest that the physiological specificity of MKP-3 for inactivation of ERK family MAP kinases reflects tight substrate binding by its N-terminal domain.

Amino Acid Sequence↗
PubMed1998

Cancer predisposition: where's the phosphate?

Mutations in a protein phosphatase and a protein kinase cause hamartomatous polyposis syndromes, which are characterised by the formation of multiple benign polyps and an increased susceptibility to some types of cancer.

Female↗
PubMed1998

The development of low birth weight term infants and the effects of the environment in northeast Brazil.

OBJECTIVES: (1) To compare the mental and psychomotor development of low birth weight term (LBW-T) infants with that of appropriate birth weight (ABW) infants at 6 and 12 months of age. (2) To examine the relationship between developmental levels and social background. METHODS: A cohort of 131 LBW-T infants (1500 to 2499 gm) and 131 ABW infants (3000 to 3499 gm) matched for sex and time of birth, recruited from six maternity centers in Northeast Brazil were followed for 1 year. Their development was assessed with the Bayley Scales at 6 and 12 months of age, and at 12 months their behavior during the test was rated on five scales. Details of their families' socioeconomic status were recorded and the degree of stimulation in their homes was assessed. RESULTS: At 6 months of age the LBW-T infants had significantly lower scores than the ABW infants on the mental development index (MDI; 4.2 points lower, p < 0.001) and on the psychomotor development index (PDI; 7.3 points lower, p < 0.001). The difference had increased by 12 months of age (MDI 7.0 points lower, p < 0.001; PDI 9.9 points lower, p < 0.001). Socioeconomic variables were related to development at both ages in both groups. Maternal literacy was significantly related to the PDI in LBW-T infants at 12 months but not in ABW infants. Similarly, stimulation in the home was related to the MDI in LBW-T infants at 6 and 12 months but not in ABW infants. LBW-T infants were less active, cooperative, vocal, and happy, and were more inhibited than ABW infants. CONCLUSIONS: LBW-T infants had poorer development than ABW infants and differed in their behavior. There was an interaction between birth weight and the environment. LBW-T infants, but not ABW infants, were affected by the quality of stimulation in the home and maternal illiteracy.

Birth Weight↗