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Biomedical subjects

M A McAleer

Publications and source records attributed to M A McAleer.

13 recordsLinked to original sources
PubMed1999

pABC11 (also known as MOAT-C and MRP5), a member of the ABC family of proteins, has anion transporter activity but does not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells.

Several members of the ABC family of proteins have been implicated in multidrug resistance associated with cancer therapies. A novel member of this gene family, designated pABC11, has been identified using degenerate polymerase chain reaction. The full-length cDNA spans 5881 base pairs and encodes an open reading frame of 1437 amino acids predicted to contain two sets of transmembrane domains and two nucleotide binding domains characteristic of ABC proteins. The nucleotide sequence described herein extends that of three recently reported sequences, MRP5 (Kool, M., de Haas, M., Scheffer, G., Scheper, R., van Eijk, M., Juijn, J., Baas, F., and Borst, P. (1997) Cancer Res. 57, 3537-3547), SMRP (Suzuki, T., Nishio, K., Sasaki, H., Kurokawa, H., Saito-Ohara, F., Ikeuchi, T., Tanabe, S., Terada, M., and Saijo, N. (1997) Biochem. Biophys. Res. Commun. 238, 790-794), and MOAT-C (Belinsky, M., Bain, L., Balsara, B., Testa, J., and Kruh, G. (1998) J. Natl. Cancer Inst. 90, 1735-1741), in the 5' direction. Northern blot analysis detected five transcripts that were differentially expressed in several tissue types, and the gene encoding pABC11 was mapped to chromosome 3. Confocal imaging of HEK293 cells expressing a green fluorescent protein-pABC11 construct confirmed plasma membrane localization of the fusion protein. Overexpression of pABC11 resulted in reduced labeling with the fluorochromes 5-chloromethylfluorescein diacetate, fluorescein diacetate, and 2',7'-bis-(2-carboxyethyl)-5 (and-6)-carboxyfluorescein acetoxymethyl ester but not with calcein or rhodamine derivatives, consistent with pABC11 being an anion transporter. Fluorochrome export was ATP-dependent but glutathione-independent. We also show that this export pump does not confer resistance to various classes of cytotoxic drugs but does provide small but significant resistance to CdCl(2) and potassium antimonyl tartrate.

ATP-Binding Cassette Transporters↗
PubMed1995

Crosses of NOD mice with the related NON strain. A polygenic model for IDDM.

Chromosome locations of non-major histocompatibility complex (MHC) genes contributing to insulin-dependent diabetes mellitus (IDDM) in mice have been determined by outcrossing NOD mice to other inbred strains congenic for the NOD MHC haplotype (H2g7). At least nine non-MHC IDDM susceptibility genes (Idd) were previously identified at first backcross (BC1) after outcross of NOD to C57BL/10.H2g7 congenic mice (B10.H2g7). We investigated whether the same set of Idd loci segregated with IDDM susceptibility after outcross of NOD to NON.H2g7 congenic mice. Since the outcrosses to NON.H2g7 and B10.H2g7 were performed in the same vivarium, direct comparisons were made of the chromosomal locations and relative strengths of Idd alleles in diabetic progeny from the two different outcrosses. In comparison with the NOD x B10.H2g7 outcross, the NOD x NON.H2g7 outcross produced significantly higher IDDM frequencies in F1, F2, and BC1 generations. The high F2 diabetes frequency allowed evaluation of the effects of homozygous expression of both the susceptibility and the resistance allele at Idd loci. This analysis demonstrated that no single non-MHC Idd locus was essential for the onset of diabetes in this cross. After outcross to NON.H2g7, Idd4 (chromosome [Chr] 11), Idd5 (Chr 1), and Idd8 (Chr 14) did not segregate with IDDM in either the BC1 or the F2 generation. Diabetogenic NOD-derived alleles at Idd2 (Chr 9), Idd3 (Chr 3), and Idd10 (Chr 3) were segregating in the BC1. An NON-derived allele contributing to susceptibility on Chr 7 (Idd7) was also detected. Dominant traits, detectable only in the F2 cross, were encoded by Chr 4 (Idd9) and two newly mapped loci on Chr 13 (Idd14) and 5 (Idd15). A third dominant trait was encoded by Chr 6 (possibly Idd6), but here, in contrast to Idd9, Idd14, and Idd15, the NON allele was diabetogenic. Stepwise logistic regression analysis of the BC1 and F2 data confirmed that the ability to identify certainty of the non-MHC Idd loci was contingent on the extent of homozygosity for NOD background genes. This study shows that the diabetogenic phenotype can be achieved through the actions of variable combinations of MHC-unlinked genes and a diabetogenic MHC haplotype.

Animals↗
PubMed1991

Genetic analysis of autoimmune type 1 diabetes mellitus in mice.

Two genes, Idd-3 and Idd-4, that influence the onset of autoimmune type 1 diabetes in the nonobese diabetic mouse have been located on chromosomes 3 and 11, outside the chromosome 17 major histocompatibility complex. A genetic map of the mouse genome, analysed using the polymerase chain reaction, has been assembled specifically for the study. On the basis of comparative maps of the mouse and human genomes, the homologue of Idd-3 may reside on human chromosomes 1 or 4 and Idd-4 on chromosome 17.

Animals↗
PubMed1991

Mononucleotide repeats are an abundant source of length variants in mouse genomic DNA.

Microsatellite sequences, such as dinucleotide repeats, show a high degree of polymorphism in eukaryotic DNA. These sequences are convenient as genetic markers and can be analyzed by the polymerase chain reaction (PCR). We have assessed the frequency of length variants in 18 mononucleotide repeats in mouse DNA and find that the variability is similar to that reported for dinucleotide repeats. Nine of the 18 repeat sequences (50%) have three or more alleles in the strains tested. Ten of these repeat sequences have been mapped using strain distribution patterns (SDPs) in recombinant inbred (RI) strains.

Animals↗
PubMed1991

Additional microsatellite markers for mouse genome mapping.

Mouse sequence information from the EMBL and GenBank databases, published sequences and genomic clones have been analyzed for simple repetitive elements or microsatellites. Each microsatellite has been amplified by the polymerase chain reaction (PCR) as a single locus marker. PCR primers were designed from unique sequence flanking each repeat. Size variation of PCR products less than 750 base pairs (bp) between mouse strains has been determined using ethidium bromide-stained acrylamide or agarose gels. A further 74 newly characterized microsatellites are presented in this paper, bringing to 185 the total we have analyzed. Of these, 157/185 (85%) have more than one allele, 143/178 (80%) vary in length between C57BL/6J and Mus spretus, and 82/168 (49%) vary between DBA/2J and C57BL/6J. Microsatellites provide informative single locus probes for linkage analysis in the construction of a genetic map of the mouse genome.

Animals↗
PubMed1990

Towards construction of a high resolution map of the mouse genome using PCR-analysed microsatellites.

Fifty sequences from the mouse genome database containing simple sequence repeats or microsatellites have been analysed for size variation using the polymerase chain reaction and gel electrophoresis. 88% of the sequences, most of which contain the dinucleotide repeat, CA/GT, showed size variations between different inbred strains of mice and the wild mouse, Mus spretus. 62% of sequences had 3 or more alleles. GA/CT and AT/TA-containing sequences were also variable. About half of these size variants were detectable by agarose gel electrophoresis. This simple approach is extremely useful in linkage and genome mapping studies and will facilitate construction of high resolution maps of both the mouse and human genomes.

Animals↗
PubMed1987

Effect of growth temperature on lipid composition and ultraviolet sensitivity of human cells.

Human skin fibroblasts were incubated at either 25 or 37 degrees C before UV irradiation. Cells incubated at 25 degrees C were more resistant to near UV radiation than cells grown at 37 degrees C, but cells grown at the lower temperature were more sensitive to 254 nm radiation. Fatty acid analysis of membranes of cells showed that cells incubated at the lower temperature contained significantly higher amounts of linoleic acid (18:2) and linolenic acid (18:3) than cells incubated at 37 degrees C. To determine if this difference in fatty acid content of the membranes was responsible for the UV survival characteristics of cells incubated at different temperatures, cells were enriched with either linoleate or linolenate during a 37 degrees C incubation period. Gas chromatography revealed that cells incorporated the supplied fatty acid. Fatty acid enriched cells were then irradiated with near UV, and survival characteristics were compared to those obtained with cells grown at the lower incubation temperature. The results suggest that the different proportion of fatty acid content of the cells is not the cause of different UV sensitivities of cells grown at 25 degrees C compared to cells grown at 37 degrees C.

Cell Division↗
PubMed1985

The response of normal and ataxia-telangiectasia human fibroblasts to the lethal effects of far, mid and near ultraviolet radiations.

The responses of two ataxia-telangiectasia (A-T) cell strains to the lethal effects of monochromatic far, mid and near ultraviolet radiations have been determined and compared with the responses of three normal human cell strains. Our results confirm a previous observation that the A-T cell strain AT4BI is abnormally sensitive to the lethal effects of mid u.v. (313 nm) radiation. After far u.v. (254 nm) radiation the strain AT4BI exhibits a small but statistically significant increase in sensitivity compared to the normal strains. Of most interest, in terms of a mechanistic interpretation of the sensitivity of A-T strains, the survival responses of neither A-T strain tested to near u.v. (365 nm) radiation differed significantly from the mean response of the normal strains, although it is of interest that one normal strain (48BR) was found to be significantly more resistant to near u.v. radiation than any of the other strains tested. The results are discussed in terms of the possible induction of radiogenic lesions in DNA by ultraviolet radiations and the possible mechanisms of radiation sensitivity in ataxia-telangiectasia.

Ataxia Telangiectasia↗