| 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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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥28,500,000 (Direct Cost: ¥28,500,000)
Fiscal Year 2004: ¥8,800,000 (Direct Cost: ¥8,800,000)
Fiscal Year 2003: ¥9,700,000 (Direct Cost: ¥9,700,000)
Fiscal Year 2002: ¥10,000,000 (Direct Cost: ¥10,000,000)
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| Keywords | Human Papillomavirus / Cancer of uterine cervix / immkortalization / E6 / E7 / telomerase / PDZ domain / トランスフォーメーション / PSD95 / DLG4 |
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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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