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Biomedical subjects

W F Dove

Publications and source records attributed to W F Dove.

At least 37 records · Page 2Linked to original sources
PubMed1996

Chemoprevention of spontaneous intestinal adenomas in the Apc Min mouse model by the nonsteroidal anti-inflammatory drug piroxicam.

C57BL/6J-Min/+mice (n = 56), heterozygous for a nonsense mutation in the Apc gene, were randomized at weaning to seven groups, including groups treated with piroxicam at 0, 50, 100, and 200 ppm in the AIN93G diet. After only 6 weeks of treatment, intestinal adenomas and aberrant crypt foci were counted, and serum levels of piroxicam and thromboxane B2 were quantitated. Tumor multiplicity was decreased in a dose-dependent manner from 17.3 +/- 2.7 in the control to 2.1 +/- 1.1 (12%) in the high-dose piroxicam group (P < 0.001). Thromboxane B2 levels in plasma also decreased monotonically in parallel to the decrease in tumor multiplicity, consistent with the prostaglandin inhibitory effect of piroxicam. The Min mouse model demonstrates that the nonsteroidal anti-inflammatory drug piroxicam has strong biological and therapeutic effects, potentially useful for prevention of the early adenoma stage of tumor development.

Animals↗
PubMed1996

Somatic genetic events linked to the Apc locus in intestinal adenomas of the Min mouse.

We have found previously that all spontaneous intestinal adenomas from Apc+/ApcMin mice lose the wild type Apc marker on two genetic backgrounds. On the (AKR x B6)F1 background, this event involves loss of the entire homolog of mouse chromosome 18 carrying Apc+. This chromosome carries both the Mcc and Dcc genes, which are homologs of genes that have been implicated in human colorectal cancer. To determine whether the loss of alleles of Mcc and/or Dcc is necessary for the formation of intestinal adenomas, subchromosomal somatic events were induced by gamma-irradiation. The observed spectrum of intrachromosomal somatic genetic losses rules out a requirement for loss of heterozygosity at either locus during adenoma formation. Subchromosomal allelic losses linked to Apc+ occur spontaneously on other genetic backgrounds. In the majority of these events, the Apc+ allele itself was somatically lost, as judged by the wild type marker at the Min site. However, on the [M. musculus castaneous (CAST) x B6-Min]F1 and (129/Sv x B6-Min)F1 backgrounds, spontaneous adenomas were observed in which the wild type marker at the Min site was retained. Further analysis will be required to determine whether these exceptions involve intra-Apc mutations. If not, then these events would illustrate routes to intestinal neoplasia that do not require complete inactivation of wild type Apc function.

Adenoma↗
PubMed1996

Manipulation of the mouse germline in the study of Min-induced neoplasia.

The Min mouse, generated by random germline mutagenesis, carries a mutation in the mouse homolog of APC and is a model of inherited human intestinal tumorigenesis. To identify other genes in the pathway(s) of intestinal tumorigenesis, genes that modify the Min phenotype have been sought. Several have been identified, including Mom1 and the genes for the 5-cytosine DNA methyltransferase and the DNA mismatch repair factor Msh2. Min-dependent tumorigenesis also occurs in mammary glands, the pancreas, and the body wall. The Min mouse has therefore become a model for tumorigenesis in a variety of organs. Identifying modifiers of its phenotype will help in piecing together the pathways of tumorigenesis in each of these tissues.

Animals↗
PubMed1996

Sulindac suppresses tumorigenesis in the Min mouse.

The Min mouse provides a genetically defined model for inherited and sporadic forms of human colorectal tumorigenesis. To test the suitability of this model for the evaluation and optimization of chemopreventive agents, we examined the effects of sulindac on tumorigenesis in Min mice as this compound can inhibit colorectal tumorigenesis in human familial adenomatous polyposis patients. Treatment of Min mice with sulindac in their drinking water (84 mg/l) or diet (167 and 334 p.p.m.) resulted in a significantly decreased average tumor load. The conservation of sulindac activity in the Min mouse provides an opportunity to explore the mechanism of sulindac suppression as well as to test other potential chemopreventive agents.

Adenomatous Polyposis Coli↗
PubMed1996

Mom1 is a semi-dominant modifier of intestinal adenoma size and multiplicity in Min/+ mice.

The intestinal tumor multiplicity in mice heterozygous for ApcMin is strongly modulated by genetic background. On the sensitive C57BL/6J (B6) background, mice develop large numbers of intestinal adenomas. The AKR/J (AKR) strain carries alleles that correlate with a strong reduction in tumor multiplicity. To study the effect of one of these modifiers, Mom1, we have generated a mouse line in which the AKR allele of Mom1 is carried on the sensitive B6 genetic background. This strain was produced by using a marker-assisted selection method to eliminate unlinked AKR alleles more rapidly. The application and efficiency of this method are discussed. We used this strain to determine that Mom1 affects both tumor multiplicity and tumor size in a semi-dominant fashion.

Adenoma↗
PubMed1996

Genetic evaluation of candidate genes for the Mom1 modifier of intestinal neoplasia in mice.

As genetic mapping of quantitative trait loci (QTL) becomes routine, the challenge is to identify the underlying genes. This paper develops rigorous genetic tests for evaluation of candidate genes for a QTL, involving determination of allelic status in inbred strains and fine-structure genetic mapping. For the Mom1 modifier of intestinal adenomas caused by ApcMin, these tests are used to evaluate two candidate genes: Pla2g2a, a secretory phospholipase, and Rap1GAP, a GTPase activating protein. Rap1GAP passes the first test but is excluded by a single fine-structure recombinant. Pla2g2a passes both tests and is a strong candidate for Mom1. Significantly, we also find that ApcMin-induced adenomas remain heterozygous for the Mom1 region, consistent with Mom1 acting outside the tumor lineage and encoding a secreted product.

Adenoma↗
PubMed1996

Action of Min and Mom1 on neoplasia in ectopic intestinal grafts.

Mice heterozygous for Min, a mutant allele of Apc, develop adenomas throughout the intestinal tract. Tumor multiplicity in Min mice is influenced by genetic modifier loci. Previously, we mapped one of these modifier loci, Mom1, to distal mouse chromosome 4. Mom1 is a semidominant modifier of both tumor size and multiplicity in Min mice. Recent evidence suggests that Mom1 may encode a secretory phospholipase, Pla2g2a. Pla2g2a is expressed in a variety of cell types and seems to be involved in inflammatory responses and bacterial defense mechanisms. Here, we determine whether Min and Mom1 act in a tissue-autonomous fashion using ectopic intestinal isografts. Within the small intestinal grafts, both Min and Mom1 act in a tissue-autonomous manner. There is no evidence that either Min or Mom1 has a systemic effect on tumor development. However, within the colonic grafts, the Min phenotype does not appear to be autonomous; the development of colonic tumors in Min mice seems dependent on factors beyond the Min genotype of the colonic epithelium. Micro-environmental factors, such as digestive secretions, dietary components, or intestinal flora, may be critical factors contributing to the development of Min-induced colonic tumors. However, these factors are not required for the action of Min or Mom1 within the small intestine.

Adenomatous Polyposis Coli Protein↗
PubMed1995

N-ethyl-N-nitrosourea treatment of multiple intestinal neoplasia (Min) mice: age-related effects on the formation of intestinal adenomas, cystic crypts, and epidermoid cysts.

The timing of intestinal tumor initiation in B6-Min/+ mice has been examined by treating mice at 5-35 days of age with a single i.p. injection of the direct-acting alkylating agent N-ethyl-N-nitrosourea (ENU). Treatment of Min/+ mice at 5-14 days of age resulted in a 3.8-fold increase in intestinal tumor multiplicity over untreated mice. Mice treated at 20-35 days of age showed only a 1.6-fold increase in tumor number. These results, in conjunction with examination of tumor multiplicities of untreated Min/+ mice as a function of age, suggest that the majority of intestinal tumors in Min/+ mice are initiated relatively early in life. Min/+ mice treated with ENU also showed an increase in the number of cystic intestinal crypts. However, the relationship between age at ENU treatment and cystic crypt multiplicity was distinct from that seen for intestinal adenomas. Mice treated at 5-9 days of age showed only a 1.9-fold increase in cystic crypts over untreated animals. By contrast, the increase in average cystic crypt multiplicity for mice treated at 10-35 days of age was 4.5-fold. In addition, 60% of Min/+ mice treated with ENU before 25 days of age developed epidermoid cysts, an extracolonic manifestation commonly associated with familial adenomatous polyposis in humans.

Adenoma↗
PubMed1995

Homozygosity for the Min allele of Apc results in disruption of mouse development prior to gastrulation.

Mutation of the APC (adenomatous polyposis coli) gene is an early event in colon tumor development in humans. Mice carrying Min (multiple intestinal neoplasia), a mutant allele of Apc, develop intestinal and mammary tumors as adults. To study the role of the Apc gene in development, we have investigated the phenotype of embryos homozygous for ApcMin (Min). Development of the primitive ectoderm fails prior to gastrulation in homozygous Min embryos. By midgestation, the presumed homozygotes consist of a mass of trophoblast giant cells with an additional cluster of much smaller embryonic cells. These results indicate that functional Apc is required for normal growth of inner cell mass derivatives.

Alleles↗
PubMed1995

Characterization of npf mutants identifying developmental genes in Physarum.

In Physarum polycephalum, uninucleate haploid amoebae develop into macroscopic multinucleate plasmodia. Wild-type, sexual development is triggered when two amoebae carrying different alleles of matA fuse to form a zygote which develops into a diploid plasmodium. Mutations in the matA genetic region give rise to apogamic strains in which a single haploid amoeba can develop into a haploid plasmodium. An essential stage in both sexual and apogamic plasmodium formation is an extended cell cycle in uninucleate cells, which ends with the formation of a binucleate cell by mitosis without cytokinesis. Using a 'brute force' screening method, we have isolated mutants blocked in apogamic plasmodium development. Genetic analysis showed that the mutations we have identified were unlinked to matA, unlike mutations previously identified following an enrichment step. Most of the loci revealed by our screen were represented by only one allele, indicating that further screening should lead to the identification of additional genes required for plasmodium development. Phenotypic analysis showed that different mutants were blocked at different stages of plasmodium formation. Some of the mutations blocking apogamic development at an early stage, close to the start of the long cell cycle, failed to block sexual development in zygotes homozygous for the mutation. Since the two modes of plasmodium formation differ only in the initiation of development, these mutations presumably interfere with the initiation process. In the remaining mutants, in which both sexual and apogamic development were blocked, development first became abnormal towards the end of the long cell cycle. This suggested that the wild-type gene products were required by this time and was consistent with previous evidence that many changes in cellular organization and gene expression occur during the long cell cycle. Each of these mutants showed a different terminal phenotype and some aspects of plasmodium development occurred normally although others were blocked, suggesting that development involves multiple pathways rather than a dependent sequence of events. Phenotypic analysis of double mutants supported this conclusion and also revealed epistatic interactions, presumably due to blocks in the same pathway. In several of the mutants, terminally differentiated cells died by an apoptosis-like mechanism; since this was never observed in vegetative cells, it was presumably triggered by the failure of development. Phenotypic analyses of additional mutants will extend our understanding of the pathways involved in plasmodium development.

Animals↗
PubMed1995

Emergent issues in the genetics of intestinal neoplasia.

Mutation of the APC gene may be a common denominator of all human colon cancer--polypoid and non-polypoid familial cancer as well as sporadic occurrences. Fearon and Vogelstein (1990) have described a series of molecular changes during the progression of human colon cancer, beginning with mutations in APC. Min is a strain of the laboratory mouse carrying a nonsense mutation in Apc, the mouse homologue of APC. The Min strain has been used to test the effect of germline alterations in certain genes identified in the progression pathway of Fearon and Vogelstein. A deficiency in DNA cytosine methylase leads to a reduction in the tumour multiplicity of Min mice contrary to the a priori expectation based on the global hypomethylation of the DNA of early colonic neoplasms. Alterations in Kras had no perceptible effect on the tumour multiplicity of Min mice but may not have been successfully directed to the proliferative cell population. Constitutional mutation of p53 did not influence the multiplicity or histopathology of early Min induced intestinal tumours. The cause and effect analysis of the genetics of colon cancer is clearly in an early phase. An unlinked genetic factor interacting with Min in controlling intestinal tumour multiplicity is Mom1. A central goal for the near future is to identify the Mom1 gene product and to identify other loci that can interact with the Min mutation and affect tumour multiplicity or progression. Mouse chimaeras will permit an analysis of the clonality and cell autonomy of Min induced neoplasms and also of the action of Mom1. The results of these analyses will inform investigators as to what modes of prevention and therapy might be designed for particular tumour types. The Min strain thereby presents an opportunity to discover protective factors against human colon cancer.

Adenomatous Polyposis Coli↗
PubMed1994

Loss of Apc+ in intestinal adenomas from Min mice.

Allelic loss at the Apc locus in spontaneously occurring intestinal adenomas from mice heterozygous for the ApcMin nonsense mutation was analyzed using a site-specific quantitative polymerase chain reaction assay. All 97 of the intestinal adenomas analyzed showed extensive loss of the wild-type Apc (Apc+) allele. Quantitative polymerase chain reaction analysis of loci linked to Apc indicated loss of the chromosome carrying Apc+. Only one copy of the homologue carrying ApcMin remained in the intestinal adenomas. Possible reasons for the difference in the mechanism of Apc+ loss between human and Min mouse intestinal adenomas are discussed.

Adenoma↗
PubMed1994

A 1.2-Mb YAC contig spans the quaking region.

We describe here a 1.2-Mb yeast artificial chromosome (YAC) contig within the region of mouse chromosome 17 between Brachyury (T) and D17Rp17e, and spanning the quaking (qk) region. We describe six new probes distributed across 1.2 Mb: D17Leh502, D17Leh503, D17Leh504, D17Leh505, D17Leh506, and D17Leh507. Probes D17Leh502 and D17Leh507 are at the extreme ends of the YAC contig. With the exception of D17Leh507, all of these probes are within a deletion associated with the quaking(viable) (qkv) allele of quaking. We have positioned these probes on a detailed YAC physical map together with two previously published probes, D17Leh508 and D17Aus119. We show here that D17Leh508 is also within the qkv deletion. Genetic mapping of D17Leh504 and D17Leh507 on two high-resolution genetic crosses carrying qkv and quaking(lethal-1) (qkl-1) alleles shows that these probes do not recombine with quaking and are therefore within 0.04 cM of qkv and 0.05 cM of qkl-1 mutations. The deletion breakpoint contained within the YAC contig has been positioned to within 90 kb by restriction mapping of wildtype and mutant DNA. This contig will form the basis for identification and mapping of expressed sequences and for an investigation of genome organization.

Alleles↗
PubMed1994

Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior.

In a search for genes that regulate circadian rhythms in mammals, the progeny of mice treated with N-ethyl-N-nitrosourea (ENU) were screened for circadian clock mutations. A semidominant mutation, Clock, that lengthens circadian period and abolishes persistence of rhythmicity was identified. Clock segregated as a single gene that mapped to the midportion of mouse chromosome 5, a region syntenic to human chromosome 4. The power of ENU mutagenesis combined with the ability to clone murine genes by map position provides a generally applicable approach to study complex behavior in mammals.

Animals↗
PubMed1993

Stable, selectable, integrative DNA transformation in Physarum.

The Physarum polycephalum actin promoter, PardC, can drive transient expression of heterologous genes in Physarum amoebae. The hph gene, encoding hygromycin (Hy) phosphotransferase, can confer resistance to Hy on a broad spectrum of organisms. When PardC is translationally fused to hph and transformed into yeasts on high-copy-number vectors, the yeasts become Hy resistant (HyR), showing that PardC-hph is a functional, selectable genetic element. To establish a stable transformation system for Physarum, we electroporated plasmids bearing PardC-hph into Physarum amoebae and then selected for HyR transformants. We show that HyR amoebae arise upon the stable integration of PardC-hph into the nuclear genome in single copy. These results establish a transformation system that can be used to add plasmid-borne genetic information to Physarum.

Actins↗
PubMed1993

ApcMin, a mutation in the murine Apc gene, predisposes to mammary carcinomas and focal alveolar hyperplasias.

ApcMin (Min, multiple intestinal neoplasia) is a point mutation in the murine homolog of the APC gene. Min/+ mice develop multiple intestinal adenomas, as do humans carrying germ-line mutations in APC. Female mice carrying Min are also prone to develop mammary tumors. Min/+ mammary glands are more sensitive to chemical carcinogenesis than are +/+ mammary glands. Transplantation of mammary cells from Min/+ or +/+ donors into +/+ hosts demonstrates that the propensity to develop mammary tumors is intrinsic to the Min/+ mammary cells. Long-term grafts of Min/+ mammary glands also gave rise to focal alveolar hyperplasias, indicating that the presence of the Min mutation also has a role in the development of these lesions.

9,10-Dimethyl-1,2-benzanthracene↗