2004 Fiscal Year Final Research Report Summary
Methodological development for the identification of disease related genes by taking advantage of chromosome abnormalities
| Project/Area Number |
12204005
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Toyama University, Faculty of Engineering |
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Principal Investigator |
ISOBE Masaharu TOYAMA UNIVERSITY, FACULTY OF ENGINEERING, PROFESSOR, 工学部, 教授 (70211050)
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| Project Period (FY) |
2000 – 2004
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| Keywords | chromosome abnormality / adult T-cell leukemia / HTLV-1 / chromosome translocation / PCR |
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| Research Abstract |
Chromosomal translocations are frequently found to be associated with various malignant disorders as well as congenital abnormalities. The characterization of chromosomal breakpoint greatly helps to identify disease related genes. To improve the step of structural characterization of a breakpoint, we have developed new method based on the adaptor-ligated polymerase chain reaction (AL-PCR). This method allowed us to complete the isolation and characterization of a breakpoint within a few days using just 100ng of patient's genomic DNA.
To prove the validity of this method, we applied this for the isolation of HTLV-1 viral integration sites in adult T-cell leukemia (ATL) patients. We isolated a total of 58 HTLV-1 integration sites using AL-PCR from 33 ATL patients and five ATL cell lines. The chromosomal target for integration was selected at random, but the integration favourably occurred within the transcription units; more than 59.5% of total integration was observed within the transcriptional unit. All inserted genes by HTLV-1 integration were expressed in normal T-cells. Upregulation of genes due to viral integration was found in two out of nine ATLL cases; about 4.4-and 102-fold elevated ankyrin-1 (ANK-1) and gephyrin ( GPHN) gene expressions were observed, respectively.
The integration of HTLV-1 is not enough to give rise a tumor. The change in expression of cellular genes is required for leukemogenesis of ATL. Thus, we applied AL-PCR for the isolation of breakpoints found in several ATL patients. From characterization of breakpoints, we found a gene named ATL1 nearby breakpoint of recurrent chromosome translocation. The ATL1 was often down regulated in ATL patient. The forced expression of ATL1 gene revealed the tumor suppressor activity in Hela cells. This suggests that the ATLI is a causative gene commonly involved in leukemogenesis of ATL.
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[Journal Article] Molecular characterization of a novel translocation t(5;14)(q21;q32) in a patient with congenital abnormalities.2006
Author(s)
Haider, S., Matsumoto, R., Kurosawa, N., Wakui, K., Fukushima, Y., Isobe, M.
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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] Frag1, a homolog of alternative replication factor C subunits, links replication stress surveillance with apoptosis.2005
Author(s)
Ishii, H., Inageta, T., Mimori, K., Saito, T., Sasaki, H., Isobe, M., Mori, M., Croce, C.M., Huebner, K., Ozawa, K., Furukawa, Y.
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Journal Title
Proc Natl Acad Sci USA 102(27)
Pages: 9655-9660
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Genetic analysis of learning and memory deficits in senescence-accelerated mouse (SAM).2005
Author(s)
Tomobe, K., Isobe, M., Okuma, Y., Kitamura, K., Oketani, Y., Nomura, Y.
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Journal Title
Physiol Behav 84(4)
Pages: 505-510
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Rapid isolation of viral integration site reveals frequent integration of HTLV-1 into expressed loci.2004
Author(s)
Ozawa, T., Itoyama, T., Sadamori, N., Yamada, Y., Hata, T., Tomonaga, M., Isobe, M.
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Journal Title
J Hum Genet 49(3)
Pages: 154-165
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Allelic imbalance of 14q32 in esophageal carcinoma.2002
Author(s)
Ihara, Y., Kato, Y., Bando, T., Yamagishi, F., Minamimura, T., Sakamoto, T., Tsukada, K., Isobe, M.
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Journal Title
Cancer Genet Cytogenet 135(2)
Pages: 177-181
Description
「研究成果報告書概要(欧文)」より
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