1999 Fiscal Year Final Research Report Summary
Molecular analysis of novel PDZ domain-containing gene encoding autoantigen of autoimmune enteropathy
| Project/Area Number |
10470052
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
MORIUCHI Tetsuya Hokkaido University, School of Medicine, Professor, 医学部, 教授 (20174394)
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| Co-Investigator(Kenkyū-buntansha) |
HAMADA Jun-ichi Hokkaido University, School of Medicine, Associate Professor, 医学部, 助教授 (50192703)
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| Project Period (FY) |
1998 – 1999
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| Keywords | LEC rat / p53 / slippage / hepatoma / polyadenine |
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| Research Abstract |
The LEC rat is a mutant strain in which hepatitis and hepatoma spontaneously develop at an extremely high incidence. Using a yeast-based assay which scores the ratio of mutants in p53 gene transcripts as red colonies, we detected frequent mutations in the liver of LEC rats. The majority of them (50-65%) were frameshift mutations caused by insertion of an extra adenine (A) and all the A insertions were found in the regions containing 6 consecutive adenines. Insertions of an extra adenine were found almost exclusively in the mRNA (cDNA), especlally in the (A)6 tract located in the most 5'-side (exon 4) among the three (A)6 tracts (exon 4, 7, and 8), and rarely in the clones of the corresponding genomic DNA part. Artifrcially synthesized p53 mRNA with the use of SP6 RNA polymerase gave insertions of an extra adenine in two clones in exon 7 and one in exon 8, but none in exon 4 out of 1 2 analyzed clones recovered from red colonies; overall accounting for 1.6% of the transcribed mRNA, indicating that the adenine insertion in exon4 (A)6 tract was an in vivo phenomenon rather than an artifact in reverse-transcription. The incidence of A insertion sharply increased up to about 20% in acute hepatitis stage, returned to control level in chronic hepatitis stage, and increased again slightly in neoplastic stage. The mutation rate correlated with serum AST level (r = 0.96, p<0.00 1) but not with contents of copper and 8-hydroxydeoxyguanosine in the liver of LEC rats. Ethanol treatment of cultured liver-derived cells also increased the rate of transcriptlonal slippage at the (A)6 tract, together suggesting that non-specific cellular damage is responsible to the increased ratios of the transcriptional mutations. These results suggest that cellular damage reduces transcriptional fidelity, thereby further enhancing the impairment of cellular functions.
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[Publications] Ba, Y., Tonoki, H., Tada, M., Nakata, D., Hamada, J. and Monuchi, T.: "Transcriptional slippage of p53 gene enhanced by cellular damage in rat liver : monitoring the slippage by a yeast functional assay."Mutation Res.. (in press).
Description
「研究成果報告書概要(欧文)」より
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[Publications] Yamamoto. K., Nakata, D., Tada, M., Tonoki, H., Nishida, T., Hirai. A., Ba, Y., Aoyama, T., Hamada J., Furuuchi, K., Harada, H., Hirai, K., Shibahara, N. Katsuoka Y. and Moriuchi, T.: "A functional and quantitative mutational analysis of p53 mutations in yeast indicates strand biases and different roles of mutations in DMBA- and BBN-Induced tumors in rat."Int. J. Cancer. 83. 700-705 (1999)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Marutani, M., Tonoki, H., Tada, M., Takahashi, M., Kashiwazaki, H., Hida, Y., Hamada J., Asaka, M. and Moriuchi T.: "Dominant negative mutations of the tumor suppressor p53 relating to early onset of glioblastoma multiforme"Cancer Res.. 59. 4765-4769 (1999)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Habelhah, H., Okada, F., Kobayashi, M., Nakai, K., Choi, S., Hamada J., Moriuchi T., Kaya, M., Yoshida, K., Fujinaga, K. and Hosokawa, M.: "Increased EIAF expression in mouse fibrosarcoma promotes metastasis through induction of MT1-MMP expression."Oncogene. 18. 1771-1776 (1999)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Shibata, T., Nagayasu, H., Kawano, T., Kitajo, H., Hamada, J., Moriuchi, T., Okada, F., Watanabe. S., Yasuda, S., Okuyama, H., Kobayashi, H. and Arisue, M.: "Unsaturated fatty acid feeding prevent the development of acute hepatitis in Long-Evans Cinnamon (LEC) rats."Anticancer Res.. (in press).
Description
「研究成果報告書概要(欧文)」より
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[Publications] Kobayashi, I., Imamura, K., Kubota, M., Ishikawa, S., Yamada, M., Tonoki, H., Okano, M., Storch, W.B. Moriuchi, T., Sakiyama, Y., Hayashi, K.: "Identification of an autoimmune enteropathy-related 75-kilodalton antigen."Gastroenterology. 117. 823-830 (1999)
Description
「研究成果報告書概要(欧文)」より
