basic research oriented for the gene therapy using of newly identified tumor suppressor human Scribble.

• Project/Area Number: 16591645
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: The University of Tokyo
• Principal Investigator: NAKAGAWA Shunsuke The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (70270874)
• Co-Investigator(Kenkyū-buntansha): YANO Tetsu The University of Tokyo, Faculty of Medicine, Associate Professor, 医学部附属病院, 助教授 (90251264)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000); Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: tumor suppressor / cell polarity / human papillomavirus / E6 oncoprotein / ubiquitin-mediated degradation / ubiquitin protein ligase / cell cycle / growth inhibition / human Scribble / 癌抑制蛋白 / LAP蛋白 / 遺伝子治療

Research Abstract

Drosophila tumor suppressor Scribble was identified as an apical-basolateral polarity determinant in epithelia. Human homologue of Drosophila Scribble, human Scribble (hScrib), has been identified as a protein targeted by human papillomavirus E6 for the ubiquitin-mediated degradation depending on E6AP, a cellular ubiquitin-protein ligase. Human Scribble is classified as a LAP protein, having leucine-rich repeats (LRRs) and PDZ domains. We investigated whether hScrib, which is thought to have a role in polarity determination based on the data of its Drosophila homologue, is involved in cell-cycle regulation and proliferation control of epithelia. Transfection of hScrib suppresses cell proliferation by blocking cell-cycle progression from G1 to S phase. We explored functional domain mapping to reveal which domains of hScrib are critical for its cellular proliferation control and localization at the basolateral membrane. We found that LRRs and PDZ domain 1 are indispensable for hScrib to inhibit cell growth by blocking cell-cycle progression and keep its proper localization. These data indicate that basolateral membrane localization of hScrib is closely related to its proliferation control. Our findings suggest the possibility that hScrib is involved in signal transduction to negatively regulate cell proliferation by localizing at basolateral membrane of epithelial cells through LRRs and PDZ domains.

Research Products

• [Journal Article] Human Scribble, a novel tumor suppressor identified as a target of high-risk HPV E6 for ubiquitin-mediated degradation, interacts with adenomatous polyposis coli (2006)
  • Author(s): Takizawa S, Nagasaka K, Nakagawa S, Yano T, Matsumoto Y, Nakagawa K, Minaguchi T, Oda K, Hiraike-Wada O, Ooishi H, Matsumoto K, Yasugi T, Taketani Y
  • Journal Title: Genes to Cells. 2006 11 Pages: 453-464
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Involvement of a cellular ubiquitin-protein ligase E6AP in the ubiquitin-mediated degradation of extensive substrates of high-risk human papillomavirus E6. (2006)
  • Author(s): Matsumoto Y, Nakagawa S, Yano T, Takizawa S, Nagasaka K, Nakagawa K, Minaguchi T, Wada O, Ooishi H, Matsumoto K, Yasugi T, Kanda T, Huibregtse JM, Taketani Y.
  • Journal Title: J Med Virol. 78(4) Pages: 501-507
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The DNA mismatch repair gene hMSH2 is a potent coactivator of oestrogen receptor alpha (2005)
  • Author(s): Wada-Hiraike O, Yano T, Nei T, Matsumoto Y, Nagasaka K, Takizawa S, Oishi H, Arimoto T, Nakagawa S, Yasugi T, Kato S, Taketani Y.
  • Journal Title: Br J Cancer. 2005 92(12) Pages: 2286-91
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Comparison between conventional surgery and radiotherapy for FIGO stage I-II cervical carcinoma : a retrospective Japanese study (2005)
  • Author(s): Yamashita H, Nakagawa K, Tago M, Shiraishi K, Nakamura N, Ohtomo K, Oda K, Nakagawa S, Yasugi T, Taketani Y.
  • Journal Title: Gynecol Oncol. 97(3)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The DNA mismatch repair gene hMSH2 is a potent coactivator of oestrogen receptor alpha (2005)
  • Author(s): Wada-Hiraike O, Yano T, Nei T, Matsumoto Y, Nagasaka K, Takizawa S, Oishi H, Arimoto T, Nakagawa S, Yasugi T, Kato S, Taketani Y.
  • Journal Title: Br J Cancer 92(12) Pages: 2286-2291
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human Scribble, a novel tumor suppressor identified as a target of high-risk HPV E6 for ubiquitin-mediated degradation, interacts with adenomatous polyposis coli (2005)
  • Author(s): Takizawa S, Nagasaka K, Nakagawa S, Yano T, Matsumoto Y, Nakagawa K, Minaguchi T, Oda K, Hiraike-Wada O, Ooishi H, Matsumoto K, Yasugi T, Taketani Y
  • Journal Title: Genes to Cells. Pages: 453-464
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Analysis of the expression and localisation of a LAP protein, human scribble, in the normal and neoplastic epithelium of uterine cervix. (2004)
  • Author(s): Nakagawa S, Yano T, Nakagawa K, Takizawa S, Suzuki Y, Yasugi T, Huibregtse JM, Taketani Y.
  • Journal Title: Br J Cancer. 90(1) Pages: 2004-2004
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Analysis of the expression and localization of a LAP protein, human scribble, in the normal and neoplastic epithelium of uterine cervix. (2004)
  • Author(s): Nakagawa S, Yano T, Nakagawa K, Takizawa S, Suzuki Y, Yasugi T, Huibregtse JM, Taketani Y.
  • Journal Title: Br J Cancer. 90(1) Pages: 194-199
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Analysis of the expression and localisation of a LAP protein, human scribble, in the normal and neoplastic epithelium of uterine cervix. (2004)
  • Author(s): Nakagawa S, Yano T et al.
  • Journal Title: British Journal of Cancer 12;90(1) Pages: 194-199
• [Journal Article] Association of PTEN mutation with HPV-negative adenocarcinoma of the uterine cervix (2004)
  • Author(s): Minaguchi T, Nakagawa S et al.
  • Journal Title: Cancer letter 8;210(1) Pages: 57-62
• [Journal Article] Methylation-associated silencing of the Wnt antagonist SFRP1 gene in human ovarian cancers. (2004)
  • Author(s): Takada T, Nakagawa S et al.
  • Journal Title: Cancer Sci. 95(9) Pages: 741-744
  • NAID: 10014197393
• [Journal Article] Molecular mechanism in carcinogenesis of the uterine cervix (2004)
  • Author(s): Nakagawa S, Taketani Y
  • Journal Title: Nippon Rinsho. 62 Suppl 10 Pages: 73-77
• [Journal Article] Preoperative diagnosis of colouterine fistula secondary to diverticulitis by sonohysterography with contrast medium. (2004)
  • Author(s): Takada T, Nakagawa S et al.
  • Journal Title: Ultrasound Obstet Gynecol. 24(6) Pages: 682-683