Biomedical subjects

Roger W Wiseman

Publications and source records attributed to Roger W Wiseman.

5 recordsLinked to original sources

PubMed2002

Frequent mutations of the Trp53, Hras1 and beta-catenin (Catnb) genes in 1,3-butadiene-induced mammary adenocarcinomas in B6C3F1 mice.

DNAs from 1,3-butadiene-induced mammary adenocarcinomas of B6C3F1 mice were examined for mutations in the Trp53 gene, the ras gene family and several components of the Wnt signaling pathway, including beta-catenin (Catnb), Apc and Axin. Trp53 mutations were detected in 41% (7 out of 17) of tumors. Each tumor with a Trp53 mutation also exhibited loss of the wild-type Trp53 allele, supporting the importance of Trp53 inactivation during development of these tumors. Analyses of the Hras1, Kras2 and Nras proto-oncogenes revealed Hras1 mutations in 53% (9 out of 17) of tumors. Seven of these mutations were a G-->C transversion in Hras1 codon 13, consistent with a 1,3-butadiene-specific Kras2 mutation previously reported in several other tumor types. Mutation screens in Catnb exon 2, the Apc mutation cluster region and the Catnb-binding domain of the Axin gene identified Catnb missense mutations in 3 out of 17 (18%) tumors. In total, mutations of the Trp53, Hras1 and/or Catnb genes were identified in 15 out of 17 1,3-butadiene-induced mammary adenocarcinomas. These results indicate that multiple genetic pathways are disrupted in chemically induced mammary tumors, and that studies in mouse models may help to understand the etiology of human breast cancers.

Adenocarcinoma↗

PubMed2002

p53 transgenic mice are highly susceptible to 1, 2-dimethylhydrazine-induced uterine sarcomas.

p53 Transgenic mice were crossed with C57BL/6J mice to investigate whether a germ-line mutation in the p53 gene predisposes for tumorigenesis in mice. (C57BL/6J x UL53-3) F(1) mice were treated with 1,2-dimethylhydrazine (DMH), a colon carcinogen. The presence of a mutant p53 led to an increased incidence or multiplicity of uterine sarcomas, colon carcinomas, lung adenomas, and hepatomas in DMH-treated mice. The most significant effect of mutant p53 was the increased incidence of uterine sarcomas, which were found in approximately 90% of p53(val135/wt) mice but only seen in approximately 10% of p53(wt/wt) mice. After examination of 15 known p53 downstream target genes in uterine sarcomas and normal uteri, we found that expression of the Reprimo gene was significantly increased in normal uteri of p53(wt/wt) mice but not in either normal uterus or uterine sarcomas of p53(val135/wt) mice. In DMH-treated animals, long-term treatment with this chemopreventive agent, piroxicam, reduced colon carcinoma incidence and multiplicity in both p53(val135/wt) or p53(wt/wt) mice but did not affect the formation of uterine sarcomas, lung adenomas, or hepatomas. These results demonstrate a tissue-specific enhancement of tumorigenesis in multiple organs by the mutant p53 transgene and additionally support the utility of (C57BL/6J x UL53-3) F(1) mice for chemoprevention studies.

1,2-Dimethylhydrazine↗

PubMed2002

Cancer susceptibility of mice with a homozygous deletion in the COOH-terminal domain of the Brca2 gene.

Inherited mutations of the human BRCA2 gene confer increased risks for developing breast, ovarian, and several other cancers. Unlike previously described Brca2 knockout mice that display predominantly embryonic lethal phenotypes, we developed mice with a homozygous germ-line deletion of Brca2 exon 27 that exhibit a moderate decrease in perinatal viability and are fertile. We deleted this Brca2 COOH-terminal domain because it interacts directly with the Rad51 protein, contains a nuclear localization signal, and is required to maintain genomic stability in response to various types of DNA damage. These homozygous Brca2-mutant mice have a significantly increased overall tumor incidence and decreased survival compared with their heterozygous littermates. Virgin female mice homozygous for this Brca2 mutation also display an inhibition of ductal side branching in the mammary gland at 6 months of age. Given their substantial viability and cancer predisposition, these mutant mice will be useful to further define the role of the COOH-terminal Brca2 domain in tumorigenesis both in vivo and in vitro.

Animals↗

PubMed2002

Are Trp53 rescue of Brca1 embryonic lethality and Trp53/Brca1 breast cancer association related?

Brca1 is involved in multiple biological pathways including DNA damage repair, transcriptional regulation, and cell-cycle progression. A complex pattern of interactions of Brca1 with Trp53 has also emerged. Xu and coworkers found that haploid loss of Trp53 significantly reduces the embryonic lethality observed in mice with a homozygous in-frame deletion of Brca1 exon 11. They report that widespread apoptosis correlates with the embryonic lethality resulting from this homozygous delta11 Brca1 mutation. A mechanism responsible for Brca1-associated carcinogenesis is proposed. These experiments extend our knowledge of a complex Brca1/Trp53 relationship. However, the precise mechanisms through which Brca1 interacts with Trp53 to suppress mammary tumor formation have yet to be elucidated.

Animals↗

PubMed2002

Thymic model for examining BRCA2 expression and function.

Mutations in the human BRCA2 breast cancer susceptibility gene are associated with increased risks of breast, ovarian, and other cancers. BRCA2 has been hypothesized to function in processes of DNA damage/breakage repair, cell proliferation, and apoptosis. These processes continually occur in the thymus during thymocyte development, and BRCA2 mRNA is highly expressed in thymus relative to most other organs. We therefore used the thymus as a model system to study BRCA2 expression and function. Quantitative reverse transcription polymerase chain reaction experiments showed that highly activated immature CD4(+) CD8(+) double-positive human thymocytes that exhibited high levels of proliferation and apoptosis had increased BRCA2 mRNA levels relative to other thymocyte subsets. BRCA2 mRNA levels were upregulated in thymocytes treated with the DNA-damaging agent etoposide. Only modest increases were associated with proliferation in human peripheral lymphocytes in response to concanavalin A (ConA) mitogen. Mice homozygous for a targeted mutation in Brca2 exon 27 (Brca2(Delta27/Delta27)) showed normal thymic architecture but had 18% decreased thymocyte cellularity compared with wild-type mice. Thymocytes from these Brca2(Delta27/Delta27) mice displayed decreased apoptosis in response to etoposide-induced DNA damage compared with wild-type thymocytes. These studies suggest that BRCA2 mRNA levels are modulated during DNA damage and may be important during apoptosis.

Animals↗