2001 Fiscal Year Final Research Report Summary
Involvement of p73-dependent apoptosis pathway in the process of acquisition of drug-resistance in human lung cancer cell lines
Project/Area Number |
12470133
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Respiratory organ internal medicine
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Research Institution | Tohoku University |
Principal Investigator |
HAGIWARA Koichi Tohoku University Hospital, Lecturer, 医学部・附属病院, 講師 (00240705)
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Co-Investigator(Kenkyū-buntansha) |
TAZAWA Ryushi Tohoku University Hospital, Reseaerch Associate, 医学部・附属病院, 助手 (70301041)
SAIJO Yasuo Tohoku University, Graduate school of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (10270828)
NUKIWA Toshihiro Tohoku University, Institute of Development, Aging and Cancer, Professor, 加齢医学研究所, 教授 (40129036)
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Project Period (FY) |
2000 – 2001
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Keywords | p73 / p63 / p53 / dominant negative / NCI-H1155 / lung cancer cell line / double mutation / transactivation activity |
Research Abstract |
p73 is a candidate tumor suppressor gene with substantial DNA and protein homology to the p53 tumor suppressor gene. In the first part of this study, we have investigated two hypotheses: (a) p73 is mutated in diverse types of human cancer, and (b) p73 is functionally redundant with p53 in carcinogenesis so that mutations would be exclusive in these two genes. The entire coding region and intronic splice junctions of p73 were examined in 54 cancer cell lines. Three lung cancer cell lines contained mutations that affected the amino acid sequence. One amino acid substitution was in a region with homology to the specific DNA binding region of p53 and two microdeletions were outside the region of homology. Two of the cell lines with p73 mutations also carried p53 mutations. Our results are inconsistent with the two hypotheses tested. Next we checked hypotheses for p63 that (a) p63 is mutated in diverse types of human cancers and (b)p63 functions in the same pathway as p53 and p73 in the pro
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cess of carcinogenesis, so that mutations in these three genes would be mutually exclusive. We analyzed the genomic structure of the p63 gene and have performed mutational analyses using the same set of cell lines as for p73. We have shown that DLD1 and SKOV3 cells have either heterozygous mutations or polymorphisms in the putative DNA binding domain of p63. In these cell lines, p63 is biallelically expressed. In the last part of the study, we analyzed three naturally occurring p73 mutants found in lung cancer cell lines. NCI-H1155 has a p73 mutation, p73(G264W), in the DNA binding domain, as well as a "gain-of-function" p53 mutation, p53(R273H). p73α(G264W) lacks the transactivation activity itself, and suppressed the transactivation activity of wild-type p73α, indicating that p73α(G264W) is a dominant negative mutant. Consistently, p73α(G264W) failed to suppress colony formation. p73 mutants found in DMS 92 or in A427 showed no functional abnormalities. In NCI-H1155 cells the coexistence of mutations that abrogate the normal function of p73 and p53 may indicate that each mutation confers an additive growth advantage on the cells. Less
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[Publications] Usui, K., Narumi, K., Saijo, Y., Koyama, S., Maemondo, M., Kikuchi, T., Tazawa, R., Hagiwara, K., Ishibashi, Y., Ohta, S., Nukiwa, T.: "N-terminal deletion augments the cell-death inducing activity of BAX in the adenoviral gene delivery to non-small cell lung cancers."Oncogene. (in press).
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「研究成果報告書概要(欧文)」より
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[Publications] Maemondo M., Narumi K., Saijo Y., Usui K., Tahara M., Tazawa R., Hagiwara K., Matsumoto K., Nakamura, T., Nukiwa T.: "Targeting angiogenesis and HGF function using an adenoviral vector expressing the HGF antagonist NK4 for cancer therapy"Mol Ther. 5. 177-85 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] Kikuchi, T., Hagiwara, K., Honda, Y., Gomi, K., Kobayashi, T., Takahashi, H., Tokue, Y., Watanabe A. and Nukiwa, T.: "Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kB tanscription factors"Journal of Antimicrobial Chemotherapy. 49. 745-755 (2002)
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「研究成果報告書概要(欧文)」より