Mieko Okamoto

Nrk: a murine X-linked NIK (Nck-interacting kinase)-related kinase gene expressed in skeletal muscle.

We report the cloning and expression pattern of a novel Ste20-type kinase gene, NIK-related kinase (Nrk), located on the mouse X chromosome. The full-length Nrk cDNA encodes a 1455-amino-acid polypeptide characterized by a N-terminal Ste20-type catalytic domain and a C-terminal regulatory domain characteristic of the group I GCK subfamily. The overall structure of the NRK protein is closely related to that of Nck-interacting kinase (Nik). In situ hybridization revealed that Nrk was predominantly expressed in skeletal muscle during mouse embryogenesis. Nrk gene expression was detected in the myotome at 10.5 dpc and, thereafter, was observed in developing skeletal musculature from 11.5 to 13.5 dpc. However, expression in skeletal muscle was not observed in adults.

Mammary Tumorigenesis in ApcMin/+ Mice is Enhanced by X Irradiation with a Characteristic Age Dependence

Abstract Imaoka, T., Okamoto, M., Nishimura, M., Nishimura, Y., Ootawara, M., Kakinuma, S., Tokairin, Y. and Shimada, Y. Mammary Tumorigenesis in ApcMin/+ Mice is Enhanced by X Irradiation with a Characteristic Age Dependence. Radiat. Res. 165, 165–173 (2006). The ApcMin/+ (Min) mouse is genetically predisposed to both intestinal and mammary tumorigenesis. We investigated age-related changes in the susceptibility of mice (before, during and after puberty) to radiation-induced mammary tumorigenesis using this model. Female Min and wild-type mice having the C57BL/6J background were irradiated with 2 Gy of X rays at 2, 5, 7 and 10 weeks and killed humanely at 18 weeks of age. Min mice irradiated at 7–10 weeks of age (after puberty) developed mammary tumors with squamous metaplasia, whereas their wild-type littermates did not. Interestingly, irradiation of Min mice at 2–5 weeks (before and during puberty, respectively) did not induce mammary tumors but rather cystic nodules with metaplasia. The mammary tumors exhibited increased nuclear β-catenin protein and loss of the wild-type Apc allele. Our results show that susceptibility to radiation-induced mammary tumorigenesis increases after puberty in Min mice, suggesting that the tumorigenic effect of ionizing radiation targets the lobular-alveolar progenitor cells, which increase in number with age and are controlled by β-catenin signaling.

Allele Loss and Kras Mutation Involved in the Development of Colorectal Tumors in Patients with Familial Adenomatous Polyposis

To investigate the mechanism of colon carcinogenesis, the loss of heterozygosity and Kras mutation were analyzed in 24 advanced FAP carcinomas, 20 advanced non-FAP carcinomas, and 111 FAP polyps with distinct histopathological dysplasia. Allele loss was observed in advanced FAP carcinomas most frequently on chromosome 5q (38%), 17p(57%), 18(36%) and 22q(35%). Non-FAP carcinomas exhibited allele losses similar to those in the FAP carcinomas. The frequency of allele loss in polyps from FAP patients was low, but it was higher in more advanced polyps; the loss was observed on chromosome 5q (24%) in severe adenomas, and on chromosome 5q (25%) and 17p(30%) in intramucosal early carcinomas. Kras mutations were detected in 50% of the advanced FAP carcinomas. The mutation frequency in polyps was lower than that in advanced carcinomas, the frequency increasing with polyp size. The present results suggest, in addition to the FAP gene on chromosome 5q, a significant role of cumulative changes in multiple tumor suppressor genes and the Kras gene during the development of colon tumors.