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Biomedical subjects

N McCabe

Publications and source records attributed to N McCabe.

10 recordsLinked to original sources
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2001

BRCA1 and GADD45 mediated G2/M cell cycle arrest in response to antimicrotubule agents.

BRCA1 is a tumour suppressor gene implicated in the predisposition to early onset breast and ovarian cancer. We have generated cell lines with inducible expression of BRCA1 to evaluate its role in mediating the cellular response to various chemotherapeutic drugs commonly used in the treatment of breast and ovarian cancer. Induction of BRCA1 in the presence of Taxol and Vincristine resulted in a dramatic increase in cell death; an effect that was preceded by an acute arrest at the G2/M phase of the cell cycle and which correlated with BRCA1 mediated induction of GADD45. A proportion of the arrested cells were blocked in mitosis suggesting activation of both a G2 and a mitotic spindle checkpoint. In contrast, no specific interaction was observed between BRCA1 induction and treatment of cells with a range of DNA damaging agents including Cisplatin and Adriamycin. Inducible expression of GADD45 in the presence of Taxol induced both G2 and mitotic arrest in these cells consistent with a role for GADD45 in contributing to these effects. Our results support a role for both BRCA1 and GADD45 in selectively regulating a G2/M checkpoint in response to antimicrotubule agents and raise the possibility that their expression levels in cells may contribute to the toxicity observed with these compounds.

Antineoplastic Agents↗
PubMed2001

Uncovering BRCA1-regulated signalling pathways by microarray-based expression profiling.

The introduction of microarray technology to the scientific and medical communities has dramatically changed the way in which we now address basic biomedical questions. Expression profiling using microarrays facilitates an experimental approach where alterations in the transcript level of entire transcriptomes can be simultaneously assayed in response to defined stimuli. We have used microarray analysis to identify downstream transcriptional targets of the BRCA1 (Breast Cancer 1) tumour-suppressor gene as a means of defining its function. BRCA1 has been implicated in the predisposition to early onset breast and ovarian cancer and while its exact function remains to be defined, roles in DNA repair, cell-cycle control and transcriptional regulation have been implied. In the current study we have generated cell lines with tetracycline-regulated, inducible expression of BRCA1 as a tool to identify genes, which might represent important effectors of BRCA1 function. Oligonucleotide array-based expression profiling identified a number of genes that were upregulated at various times following inducible expression of BRCA1 including the DNA damage-responsive gene GADD45 (Growth Arrest after DNA Damage). Identified targets were confirmed by Northern blot analysis and their functional significance as BRCA1 targets examined.

BRCA1 Protein↗
PubMed1996

Natural history of isolated bundle branch block.

The purpose of this study was to determine the long-term outcome of patients with bundle branch block (BBB) who have no clinical evidence of cardiovascular disease. Among 110,000 participants in a screening program, 310 subjects with BBB without apparent of suspected heart disease were identified. Their outcome after a mean follow-up of 9.5 years was compared with that of 310 similarly screened age- and sex-matched controls. Among the screened population, isolated right BBB was more prevalent than isolated left BBB (0.18% vs 0.1%, respectively; p<0.001), and the prevalence of each abnormality increased with age (p<0.001). Total actuarial survival was no different for those with left BBB or right BBB and their respective controls. Cardiac mortality, however, was increased in the left BBB group when compared with their controls (p=0.01, log rank test). Left BBB, but not right BBB, was associated with an increased prevalence of cardiovascular disease at the follow-up (21% vs 11%; p=0.04). In the absence of clinically overt cardiac disease, the presence of left BBB or right BB is not associated with increased overall mortality. Isolated left BBB is associated with an increased risk of developing overt cardiovascular disease and increased cardiac mortality.

Adult↗
PubMed1995

The human MLL gene: nucleotide sequence, homology to the Drosophila trx zinc-finger domain, and alternative splicing.

We have previously reported the cloning of several cDNAs corresponding to the MLL gene. The predicted primary amino acid sequence of two of these clones, 14p-18B and 14-7, reveals nearly complete identity with parts of the sequences of HRX, ALL-1, and Htrx-1, including a Zinc-finger region with homology to the Drosophila trithorax gene. However, we found that there is a stretch of 39 amino acids that is absent from 14p-18B when compared to ALL-1 and HRX. Another sequence of three amino acids is present in ALL-1, but is absent from 14p-18B and HRX. Nucleotide sequence examination reveals that these differences arise from alternative splicing, suggesting that MLL, HRX, and ALL-1 each represents a different alternative splicing product from the same gene. At least two cDNA clones, 14-7 and 14p-18C, correspond to incompletely processed transcripts including intron sequences. Northern blots using a subclone of 14p-18B revealed mRNA species of 14-16 kb in size in various human tissues. RNase protection assays show that the splice variant containing exon 8 and lacking a 9-bp extension 3' of exon 12 is predominantly expressed in hematopoietic cell lines.

Alternative Splicing↗
PubMed1993

Identification of the gene associated with the recurring chromosomal translocations t(3;14)(q27;q32) and t(3;22)(q27;q11) in B-cell lymphomas.

Chromosomal translocations involving chromosome 3, band q27, are among the most common rearrangements in B-cell non-Hodgkin lymphoma. From a bacteriophage lambda library prepared from a lymphoma characterized by a t(3;14)(q27;q32), genomic clones were isolated using a probe from the immunoglobulin heavy chain locus (IGH) joining region. In addition to clones containing an apparently normal IGH rearrangement, others were found to contain one of the translocation breakpoint junctions. Normal chromosome 3 sequences and the reciprocal breakpoint junction were subsequently isolated. DNA probes on each side of the chromosome 3 breakpoint hybridized at high stringency to the DNA of various mammalian species, demonstrating evolutionary conservation. One such probe from the presumptive der(3) chromosome detected an 11-kilobase transcript when hybridized to RNA of B- and T-cell lines. A probe made from partial cDNA clones isolated from a T-cell line hybridized with genomic DNA from both sides of the chromosome 3 breakpoint, indicating that the t(3;14) is associated with a break within the gene on chromosome 3. In situ chromosomal hybridization revealed that the same gene is involved in the t(3;22)(q27;q11). Preliminary nucleotide sequencing shows no identity of the cDNA to gene sequences in available data banks. We propose the name BCL6 (B-cell lymphoma 6) for this gene, since it is likely to play a role in the pathogenesis of certain B-cell lymphomas.

Animals↗
PubMed1988

Extent and limits of cerebral adjustment to early section or congenital absence of the corpus callosum.

The ability to effect inter- and intrahemispheric comparisons of visual and tactile stimuli was studied in 4 callosotomized patients and 6 callosal agenesis subjects using response accuracy and response times to determine the extent of cerebral adjustment to functional or congenital absence of the corpus callosum. The visual tasks involved within- and between-fields presentation of pairs of colours and shapes. The tactile tasks required uni- and bimanual comparisons of 3 categories of stimuli (size, shape and texture) of increasing difficulty. Older callosotomized children showed disconnection deficits similar to those reported in adult split-brain patients, whereas both acallosal subjects and our youngest patient with complete callosal transection demonstrated a high level of accuracy in the interhemispheric tasks. However, all patients required considerably more time to accomplish the cross-integration of relatively complex visual and tactile information which seems to be one of the major limitations of the compensatory mechanisms. The results also indicate that the quality of transfer differs between the acallosal and early-callosotomized patients in relation to the sensory modality studied. Thus, visual cross-matching was found to be superior to bimanual matching for the callosotomized group, whereas intermanual comparisons proved to be more efficient than visual integration in the acallosals. These divergent findings suggest not only that different compensatory mechanisms may be operating in visual and tactile transfer, but also that the same mechanisms may be utilized differently by the two populations deprived of the use of callosal connections.

Adolescent↗
PubMed1987

Phorbol ester stimulates proliferation of astrocytes in primary culture.

Near-confluent primary cultures of astrocytes from the neonatal rat cerebral cortex were transferred to low serum (0.1%) growth medium for 24 h before a single addition of phorbol-12-myristate-13-acetate (0.01-100 ng X ml-1), a phorbol ester which mimics diacylglycerol activation of protein kinase C. After 48 h the cultures were pulsed with [methyl-3H]thymidine. Cultures exposed to phorbol ester exhibited dose-dependent increases in thymidine incorporation which were reversed by amiloride.

Amiloride↗
PubMed1987

Increased fucosylation of chick brain proteins following training: effects of cycloheximide.

When chicks are trained to avoid pecking a bead coated with methylanthranilate in a one-trial passive avoidance task there is an increase in fucose incorporation in vivo and in vitro in the right forebrain base of methylanthranilate (M)-trained compared to water (W)-trained chicks. The relation of this increase to de novo protein synthesis in vivo and in vitro has been examined. Cycloheximide (Cx), 1 mM, inhibited in vitro fucosylation of chick brain slices by 60% after 3 h. However, the training-related increase in in vitro fucosylation still persisted. When Cx was injected intraventricularly 10 min before training, the subsequent increase in in vitro fucosylation due to training was still apparent. When Cx was injected and [14C]leucine and [3H]fucose incorporation studied in vivo in M-trained and W-trained chicks, there was no increase in fucosylation due to training in the Cx-treated M-trained over the W-trained chicks. These results are taken to indicate that in vitro fucosylation and its increase subsequent to training is not protein synthesis-dependent, but that both in vivo and in vitro there are interactions between Cx and fucosylation steps that are independent of Cx's effects on protein synthesis.

Animals↗