2004 Fiscal Year Final Research Report Summary
Analyzing mechanism of oncogenesis by human papillomavirus
| Project/Area Number |
14026065
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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 | National Cancer Center Research Institute |
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Principal Investigator |
KIYONO Tohru National Cancer Center Research Institute, Virology Division, Chief, ウイルス部, 部長 (10186356)
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| Co-Investigator(Kenkyū-buntansha) |
NARISAWA Mako (SAITO Mako) National Cancer Center Research Institute, Virology Division, Reseacher, ウイルス部, 研究員 (50283023)
YUGAWA Takashi national cancer center research institute, virology division, Reseacher, ウイルス部, 研究員 (80311372)
YAMASHITA Yoriko Nagoya University, Graduate School of Malicine, Assistant, 大学院医学研究科, 助手 (90303643)
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| Project Period (FY) |
2002 – 2004
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| Keywords | Human Papillomavirus / Cancer of uterine cervix / immkortalization / E6 / E7 / telomerase / PDZ domain |
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| Research Abstract |
Transforming activity of E6 requires the PDZ-binding motif at the carboxy terminus conserved among high risk HPV E6 proteins. Since we first reported the hDLG as the E6 target, hScrib, MUPP1, and MUGI have been reported as the similar targets. We identified PSD95 as a novel target. The fact that HPV positive cervical cancer cell lines showed very low expression levels of PSD95, allowed us speculate that PSD95 might function as tumor suppressor. Overexpression of PSD95 in CaSki cells unchanged the growth in a culture dish but significantly reduced the growth both in soft agar medium and nude mice. It was also suggested that PSD95 was ubiquitinated by E6/E6AP complex and degraded by proteosome.
It has long been unknown how E6 activates telomerase in normal human keratinocyte and mammary epithelial cells. We found that E6/E6AP complex bound to a transcriptional repressor, NFX-1. From NIX-1 gene, 123 kDa (NFX1-123) and 91kDa (NFX1-91) proteins were expressed. We found E6/E6AP complex specifically enhanced degradation of NFX1-91 which functioned as transcriptional repressor of hTERT promoter, indicating that the enhanced degradation of NFX-1 is at least a mechanism to activate telomerase by E6.
We suggest that the upregulation of hWAPL, which is preferentially overexpressed in cervical cancers, might be a mechanism which induces chromosomal instability in normal cells by E6 and E7. Human WAPL (hWAPL) is a human homologue of Drosophila wing apart-like gene. The gene product binds to heterochromatin and its overexpression can induce chromosomal instability in cultured cells.
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Research Products
(17 results)
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[Journal Article] The human papillomavirus E6 and E7 inducible oncogene, hWAPL, exhibits potential as a therapeutic target.2005
Author(s)
Kuroda, M., Kiyono, T, Oikawa, K., Yoshida, K., Mukai, K.
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Journal Title
Br.J.Cancer Res. 92
Pages: 290-293
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Expression of a novel human gene, h WAPL, is associated with cervical carcinogenesis and tumor progression.2004
Author(s)
Oikawa, K., Ohbayashi, T., Kiyono, T., Nishi, H., Isaka, K., Umezawa, A., Kuroda, M., Mukai, K.
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Journal Title
Cancer Res. 64
Pages: 3545-9
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Gojo, S., Miyoshi, S., Ita, M., Segawa, K., Ogawa, S., Sakamoto, M., Nakamura, S., and Umezawa, A. Can the life-span of human marrow stromal cells be prolonged by bmi-1, E6, E7, and/or telomerase without affecting cardiomyogenic differentiation?2004
Author(s)
Takeda, Y., Mori, T.Imabayashi, H, Kiyono, T.
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Journal Title
J.Gene Med. 6
Pages: 833-45
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Nishiyama, Y., and Tsurumi T. Inhibition of S-phase cyclin-dependent kinase activity blocks expression of Epstein-Barr virus immediate-early and early genes, preventing viral lytic replication.2004
Author(s)
Kudoh, A., Daikoku, T., Sugaya, Y, Isomura, H., Fujita, M., Kiyono, T.
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Journal Title
J.Virol 78
Pages: 104-115
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Combination of hTERT and Bmi-1, E6 or E7 induce prolongation of the life span of bone marrow stromal cells from an elderly donor without affecting their neurogenic potential.
Author(s)
Mori T, Kiyono T, Imabayashi H, Takeda Y, Tsuchiya K, Miyoshi S, Makino H, Matsumoto K, Saito H, Ogawa S, Sakamoto M, Hata J, Umezawa A.
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Journal Title
Mol Cell Biol. (in press)
Description
「研究成果報告書概要(欧文)」より
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