Wild type N-ras as a tumor suppressor in human sporadic medullary thyroid cardnoma
| Project/Area Number |
18390101
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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 |
Pathological medical chemistry
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| Research Institution | Kyoto University |
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Principal Investigator |
TAKAHASHI Chiaki Kyoto University, Graduate School of Medicine, Associate Professor (50283619)
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| Co-Investigator(Kenkyū-buntansha) |
AWAD Shamma Kyoto University, Graduate School of Medicine, Assistant Professor (50402839)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,330,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2007: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2006: ¥7,100,000 (Direct Cost: ¥7,100,000)
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| Keywords | oncogene / tumor suppressor / ras / mdullary thyroiod carcinoma / senescence / DNA damage / malignant conversion / Rb / 悪性化 / がん抑制遺伝子 / ノックアウトマウス / 甲状腺髄様癌 |
|---|
| Research Abstract |
Aberration of the retinoblastoma (Rb) pathway critically pertains to human carcinogenesis. However, the genetic evidence of Rb inactivation is found in an unexpectedly limited variety of malignant tumors, implicating a requirement of additional changes for robust clonal expansion by Rb-deficient cells. Rb-heterozygous mice produce C-cell adenoma in thyroid as a consequence of biallelic loss of Rb. We previously reported that additional deletion of N-ras in Rb-heterozygous mice resulted in malignant conversion in C-cell adenoma. To clarify the mechanism underlying the tumor suppressor function of wild type N-ras, we intensively characterized primary tumors from our genetically modified mice and also from human medullary thyroid carcinoma patients. As the results of our study, we propose here the mechanism by which at least murine C-cells and fibroblasts are protected from Rb-loss-induced carcinogenesis by the presence of N-ras loci. In the absence of Rb, N-Ras activity is increased in E2F-dependent manner, inducing DNA damage response and cellular senescence yet in a manner clearly distinct from its constitutively activated form. These findings assign a critical role for wild type N-ras in controlling malignant conversion of tumors upon pRb inactivation. In human sporadic medullary thyroid carcinomas in which ret oncogene mutation is less frequent than in familial cases, we previously detected 10 cases with Rb-N-ras double LOH out of 18 cases by using micro satellite markers flanking each gene. In this study, we obtained more number of samples (18 adenocarcinomas and 2 adenomas) from Tokyo Women's Medical College in an aim to perform more detailed immunohistochemical and genetic analyses. This line of investigation addresses whether N-ras acts as tumor suppressor in human cancers. Currently, we are acutely accumulating considerable amount of information from newly obtained clinical samples.
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Report
(3 results)
Research Products
(43 results)
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[Journal Article] Localization of the membrane-anchored MMP-regulator RECK at the neuromuscular junctions2008
Author(s)
S., Kawashima, T., Noda, E., Chandana, Y., Imamura, R., Takahashi, E., Adachi, C., Takahashi, M., Noda
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Journal Title
J. Neurochem 104 :
Pages: 376-385
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] RECK modulates the Notch signal during cortical neurogenesis2007
Author(s)
T., Muraguchi, Y., Takegami, E. P. S., Chandana, S., Kitajima, A., Omura, T., Mild, R., Takahashi, N., Matsumoto, A., Ludwig, M., Noda,C., Takahashi
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Journal Title
Nature Neuroscience 10 :
Pages: 836-845
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] RECK regulates cell surface activity of MT1-MMP and CD13 by dual mechanisms2007
Author(s)
T., Miki, Y., Takegami, K, Okawa, T., Muraguchi, M., Noda, C., Takahashi
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Journal Title
J. Biol.Chem. 282
Pages: 12341-12352
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] MMP-2 plays a critical role in the pathogenesis of white matter lesions alter chronic cerebral hypoperfusion in the rodent2006
Author(s)
K, Nakaji, M., lhara, C., Takahashi. S., Itohara, M., Noda, R., Takahashi, H., Tomimoto
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Nras loss induces metastatic conversion of Rbl- deficient neuroendocrine thyroid tumor2006
Author(s)
C., Takahashi, B., Contreras, T., Iwanaga, Y., Takegami, A., Bakker, R. T., Bronson, M., Noda, M., Loda, J. L., Hunt, M. E., Ewen
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Journal Title
Nature Genetics 38
Pages: 118-123
Description
「研究成果報告書概要(欧文)」より
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