Identification and functional analysis of a novel human dependence receptor and its application to the therapeutic strategy

• Project/Area Number: 19390289
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: NAKAGAWARA Akira Chiba Cancer Center (Research Institute), 研究局, 研究局長 (50117181)
• Co-Investigator(Kenkyū-buntansha): 中村 洋子 千葉県がんセンター(研究所), 生化学研究部, 主席研究員 (60260254)
• Co-Investigator(Renkei-kenkyūsha): NAKAMURA Yohko 千葉県がんセンター(研究所), 研究局, 主席研究員 (60260254)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2008: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2007: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: 依存性受容体 / Unc5H / 細胞死 / 自然退縮 / 神経芽腫

Research Abstract

独自に作製した神経芽腫cDNA librarykaraから同定した新規依存性受容体UNC5Dについて、機能を解析した。
その結果、UNC5DはNGF欠乏による細胞死(プログラム細胞死)やDNA損傷時に活性化されるp53によって発現が誘導され、ガスパーゼによって切断された細胞内断片は核へ移動し、pro-apoptoticなターゲット遺伝子の発現を誘導した。
神経芽腫の自然退縮を促進する重要な分子機構と思われた。

Research Products

• [Journal Article] Rousseau R, Combaret V, Puisieux A, Valteau-Couanet D, Benard J, Bernet A, Mehlen P. Netrin-1 acts as a survival factor for aggressive neuroblastoma (2009)
  • Author(s): Delloye-Bourgeois C, Nakagawara A, et al
  • Journal Title: J. Exp. Med 206 Pages: 833-847
  • Peer Reviewed
• [Journal Article] International consensus for neuroblastoma molecular diagnostics: Report from the international neuroblastoma risk grouping (INRG) biology committee (2009)
  • Author(s): Ambros PF, Nakagawara A, et al
  • Journal Title: Br. J. Cancer 100 Pages: 1471-1482
  • Peer Reviewed
• [Journal Article] Distinct role of ShcC docking protein in the differentiation of neuroblastoma (2009)
  • Author(s): Miyake I, Nakagawara A et al
  • Journal Title: Oncogene 28 Pages: 662-673
  • Peer Reviewed
• [Journal Article] High expression of ncRAN, a novel non-coding RAN mapped to chromosome 17q25. 1, is associated with poor prognosis in neuroblastoma (2009)
  • Author(s): Yu M, Nakamura Y Nakagawara A, et al
  • Journal Title: Int. J. Oncol 34 Pages: 931-938
  • Peer Reviewed
• [Journal Article] Distinct role of ShcC docking protein in the differentiation of neuroblastoma (2009)
  • Author(s): Miyake I., Nakagawara A., et al.
  • Journal Title: Oncogene 28 Pages: 662-673
  • Peer Reviewed
• [Journal Article] Netrin-1 acts as a survival factor for aggressive neuroblastoma (2009)
  • Author(s): Delloye-Bourgeois C., Nakagawara A., et al.
  • Journal Title: J. Exp. Med. 206 Pages: 833-847
  • Peer Reviewed
• [Journal Article] Report from the international neuroblastoma risk grouping (INRG) biology committee (2009)
  • Author(s): Ambros PF., Nakagawara A., et al.
  • Journal Title: Br. J. Cancer (in press)
  • Peer Reviewed
• [Journal Article] Clinicopathological relevance of UbcH10 in breast cancer (2008)
  • Author(s): Fujita T, NakagawaraA, et al
  • Journal Title: Cancer Sci (Epub ahead of print)
  • NAID: 10025142238
  • Peer Reviewed
• [Journal Article] Loss of imprinting of IGF2 correlates with hypermethylation of the H19 differentially methylated region in hepatoblastoma (2008)
  • Author(s): Honda S, Nakagawara A, et al
  • Journal Title: Br. J. Cancer 99 Pages: 1891-1899
  • Peer Reviewed
• [Journal Article] factor for human neuroblastoma (2008)
  • Author(s): Ikematsu S, nakagawara A, nakamura Y, et al
  • Journal Title: Cancer Sci 99 Pages: 2070-2074
  • Peer Reviewed
• [Journal Article] Oncogenic mutations of ALK kinase in neuroblastoma (2008)
  • Author(s): Chen Y, Nakagawara A, et al
  • Journal Title: Nature 455 Pages: 971-974
  • Peer Reviewed
• [Journal Article] KIF1Bβ functions as a haploinsufficient tumor suppressor gene mapped to chromosome 1p36. 2 by inducing apoptotic cell death (2008)
  • Author(s): Munirajan AK, Nakagawara A, et al
  • Journal Title: J. Biol. Chem 283 Pages: 24426-24434
  • Peer Reviewed
• [Journal Article] Expression of TSLC1, a candidate tumor suppressor gene mapped to chromosome 11q23, is downregulated in unfavorable neuroblastoma without promoter hypermethylation (2008)
  • Author(s): Ando K, Nakamura Y, nakagawara A, et al
  • Journal Title: Int. J. Cancer 123 Pages: 2087-2094
  • Peer Reviewed
• [Journal Article] N-MYC promotes cell proliferation through adirect transactivation of neuronal leucine-rich repeat protein-1 (NLRR1) gene in neuroblastomaneuroblastoma. Oncogene (2008)
  • Author(s): Hossain MS, Nakagawara A, et al
  • Journal Title: Oncogene 27 Pages: 6075-6082
  • Peer Reviewed
• [Journal Article] Alterations in the glycoform of cisplatin-resistant human carcinoma cells are caused by defects in the endoplasmic reticulum- associated degradation system (2008)
  • Author(s): Nakagawa H, Nakagawara A, et al
  • Journal Title: Cancer Lett 270 Pages: 295-301
  • Peer Reviewed
• [Journal Article] NFBD1MDC1 stabilizes oncogenic MDM2 to contribute to cell fate determination in response to DNA damage. Biochem.Biophys (2008)
  • Author(s): Inoue K, Nakagawara A, et al
  • Journal Title: Res.Commun 371 Pages: 829-833
  • Peer Reviewed
• [Journal Article] Inhibitory role of Plk1 in the regulation of p73-dependent apoptosis through physical interaction and phosphorylation (2008)
  • Author(s): Koida N, Nakagawara A, et al
  • Journal Title: J. Biol. Chem 283 Pages: 8555-8563
  • Peer Reviewed
• [Journal Article] Identification of genes targeted by CpG island methylator phenotype in neuroblastomas, and their possible integrative involvement in poor prognosis (2008)
  • Author(s): Abe M, Nakagawara A, et al
  • Journal Title: Oncology 74 Pages: 50-60
  • Peer Reviewed
• [Journal Article] A newly identified dependence receptor UNC5H4 is induced during DNA damage-mediated apoptosis and transcriptional target of tumor suppressor p53. Biochem (2008)
  • Author(s): Wang H, Nakagawara A, et al
  • Journal Title: Biophys. Res. Commun 370 Pages: 594-598
  • Peer Reviewed
• [Journal Article] The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients (2008)
  • Author(s): Honda S, Nakagawara A, et al
  • Journal Title: Int. J. Cancer 123 Pages: 1117-1125
  • Peer Reviewed
• [Journal Article] △Np63/BMP-7-dependent expression of matrilin-2 is involved in keratinocyte migration in response to wounding. Biochem. Biophys (2008)
  • Author(s): Ichikawa T, Nakagawara A, et al
  • Journal Title: Res. Commun 369 Pages: 994-1000
  • Peer Reviewed
• [Journal Article] A novel HECT-type E3 ubiquitin protein ligase NEDL1 enhances the p53-mediated apoptotic cell death in its catalytic activity-independent manner (2008)
  • Author(s): Li Y, Nakagawara A, et al
  • Journal Title: Oncogene 27 Pages: 3700-3709
  • Peer Reviewed
• [Journal Article] Activation of AMP-activated protein kinase induces p53-dependent apoptotic cell death in response to energetic stress (2008)
  • Author(s): Okoshi R, Nakagawara A, et al
  • Journal Title: J. Biol. Chem 283 Pages: 3979-3987
  • Peer Reviewed
• [Journal Article] Sp1-mediated transcriptional rggulation of NFBD1/MDC1 plays a critical role in DNA damage response pathway (2008)
  • Author(s): Bu Y, Nakagawara A
  • Journal Title: Genes to cells 13 Pages: 53-66
  • Peer Reviewed
• [Journal Article] Stress via p53 pathway causes apoptosis by mitochondrial Noxa upregulation in doxorubicin-treated neuroblastoma cells (2008)
  • Author(s): Kurata K, Nakagawara
  • Journal Title: Oncogene 27 Pages: 741-754
  • Peer Reviewed
• [Journal Article] ERAP140/Nbla10993 is a novel favorable probnostic indicator for neuroblastoma induced in response to retinoic acid (2008)
  • Author(s): Arai H, nakamura Y, Nakagawara
  • Journal Title: Oncogene 19 Pages: 1381-1388
  • Peer Reviewed
• [Journal Article] ATM-dependent nuclear accumulation of IKK-α plays an important role in the regulation of p73-mediated apoptosis in response to cisplatin (2008)
  • Author(s): Yoshda K, Nakagawara A
  • Journal Title: Oncogene 27 Pages: 1183-1188
  • Peer Reviewed
• [Journal Article] novel risk stratification of patients with neuroblastoma by genomic signature, which is independent of molecular signature (2008)
  • Author(s): Tomioka N, Nakamura Y, Nakagawara A
  • Journal Title: Oncogene 27 Pages: 441-449
  • Peer Reviewed
• [Journal Article] Tap63-dependent induction of growth differentiation factor 15 (GDF15) plays a critical role in the regulation of keratinocyte differentiation (2008)
  • Author(s): Ichikawa T, Nakagawara A
  • Journal Title: Oncogene 27 Pages: 409-420
  • Peer Reviewed
• [Journal Article] TAp63-dependent induction of growth differentiation factor 15 (GDF15) plays a critical role in the regulation of keratinocyte differentiation (2008)
  • Author(s): Ichikawa T., Nakagawara A., et al.
  • Journal Title: Oncogene 27 Pages: 409-420
  • Peer Reviewed
• [Journal Article] Novel risk stratification of patients with neuroblastoma by genomic signature, which is independent of molecular signature (2008)
  • Author(s): Tomioka N., Nakagawara A., et al.
  • Journal Title: Oncogene 27 Pages: 441-449
  • Peer Reviewed
• [Journal Article] ATM-dependent nuclear accumulation of IKK-α plays an important role in the regulation of p73-mediated apoptosis in response to cisplatin (2008)
  • Author(s): Yoshida K., Nakagawara A., et al.
  • Journal Title: Oncogene 27 Pages: 1183-1188
  • Peer Reviewed
• [Journal Article] ERAP140/Nbla10993 is a novel favorable prognostic indicator for neuroblastoma and induced in response to retinoic acid (2008)
  • Author(s): Arai H., Nakagawara A., et al.
  • Journal Title: Oncol. Rep. 19 Pages: 1381-1388
  • Peer Reviewed
• [Journal Article] Stress via p53 pathway causes apoptosis by mitochondrial Noxa up-regulation in doxorubicin-treated neuroblastoma cells (2008)
  • Author(s): Kurata K., Nakagawara A., et al.
  • Journal Title: Oncogene 27 Pages: 741-754
  • Peer Reviewed
• [Journal Article] Sp1-mediated transcriptional regulation of NFBD1/MDC1 plays a critical role in DNA damage response pathway (2008)
  • Author(s): Bu Y., Nakagawara A., et al.
  • Journal Title: Genes Cells 13 Pages: 53-66
  • Peer Reviewed
• [Journal Article] Activation of AMP-activated protein kinase Lnduces p53-dependent Apoptotic Cell Death in Response to Energetic Stress (2008)
  • Author(s): Okoshi R., Nakagawara A., et al.
  • Journal Title: J. Biol. Chem 283 Pages: 3979-3987
  • Peer Reviewed
• [Journal Article] A novel HECT-type E3 ubiquitin protein ligase NEDL1 enhances the p53-mediated apoptotic cell death in its catalytic activity-independent manner (2008)
  • Author(s): Li Y., Nakagawara A., et al.
  • Journal Title: Oncogene 27 Pages: 3700-3709
  • Peer Reviewed
• [Journal Article] DeltaNp63/BMP-7-dependent expression of matrilin-2 is involved in keratinocyte migration in response to wounding (2008)
  • Author(s): Ichikawa T., Nakagawara A., et al.
  • Journal Title: Biochem. Biophys. Res. Commun. 369 Pages: 994-1000
  • Peer Reviewed
• [Journal Article] The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients (2008)
  • Author(s): Honda S., Nakagawara A., et al.
  • Journal Title: Int. J. Cancer 123 Pages: 1117-1125
  • Peer Reviewed
• [Journal Article] A newly identified dependence receptor UNC5H4 is induced during DNA damage-mediated apoptosis and transcriptional target of tumor suppressor p53 (2008)
  • Author(s): Wang H., Nakagawara A., et al.
  • Journal Title: Biochem. Biophys. Res. Commun. 370 Pages: 594-598
  • Peer Reviewed
• [Journal Article] Identification of genes targeted by CpG island methylator phenotype in neuroblastomas, and their possible integrative involvement in poor prognosis (2008)
  • Author(s): Abe M., Nakagawara A., et al.
  • Journal Title: Oncogene 74 Pages: 50-60
  • Peer Reviewed
• [Journal Article] Inhibitory role of Plk1 in the regulation of p73-dependent apoptosis through physical interaction and phosphorylation (2008)
  • Author(s): Koida N., Nakagawara A., et al.
  • Journal Title: J. Biol. Chem. 283 Pages: 8555-8563
  • Peer Reviewed
• [Journal Article] NFBD1/MDC1 stabilizes oncogenic MDM2 to contribute to cell fate determination in response to DNA damage (2008)
  • Author(s): Inoue K., Nakagawara A., et al.
  • Journal Title: Biochem. Biophys. Res. Commun. 371 Pages: 829-833
  • Peer Reviewed
• [Journal Article] Alterations in the glycoform of cisplatin-resistant human carcinoma cells are caused by defects in the endoplasmic reticulum-associated degradation system (2008)
  • Author(s): Nakagawa H., Nakagawara A., et al.
  • Journal Title: Cancer Lett. 270 Pages: 295-301
  • Peer Reviewed
• [Journal Article] N-MYC promotes cell proliferation through a direct transactivation of neuronal leucine-rich repeat protein-1 (NLRR1) gene in neuroblastoma (2008)
  • Author(s): Hossain MS., Nakagawara A., et al.
  • Journal Title: Oncogene 27 Pages: 6075-6082
  • Peer Reviewed
• [Journal Article] Expression of TSLC1, a candidate tumor suppressor gene mapped to chromosome 11q23, is downregulated in unfavorable neuroblastoma without promoter hypermethylation (2008)
  • Author(s): Ando K., Nakagawara A., et al.
  • Journal Title: Int. J. Cancer 123 Pages: 2087-2094
  • Peer Reviewed
• [Journal Article] KIF1Bβ functions as a haploinsufficient tumor suppressor gene mapped to chromosome 1p36. 2 by inducing apoptotic cell death (2008)
  • Author(s): Munirajan AK., Nakagawara A., et al.
  • Journal Title: J. Biol. Chem. 283 Pages: 24426-24434
  • Peer Reviewed
• [Journal Article] Oncogenic mutations of ALK kinase in neuroblastoma (2008)
  • Author(s): Chen Y., Nakagawara A., et al.
  • Journal Title: Nature 455 Pages: 971-974
  • Peer Reviewed
• [Journal Article] Plasma midkine level is a prognostic factor for human neuroblastoma (2008)
  • Author(s): Ikematsu S., Nakagawara A., et al.
  • Journal Title: Cancer Sci. 99 Pages: 2070-2074
  • NAID: 10024012365
  • Peer Reviewed
• [Journal Article] Loss of imprinting of IGF2 correlates with hypermethylation of the H19 differentially methylated region in hepatoblastoma (2008)
  • Author(s): Honda S., Nakagawara A., et al.
  • Journal Title: Br. J. Cancer 99 Pages: 1891-1899
  • Peer Reviewed
• [Journal Article] High expression of ncRAN, a novel non-coding RNA mapped to chromosome 17q25. 1, is associated with poor prognosis in neuroblastoma (2008)
  • Author(s): Yu M., Nakagawara A., et al.
  • Journal Title: Int. J. Oncol. 34 Pages: 931-938
  • Peer Reviewed
• [Journal Article] Novel risk stratificatlon of patients with neuroblastoma by genomic signature,which is independent of molecular signature. (2008)
  • Author(s): Tomioka N, Nakagawara A, 他14名、16番目
  • Journal Title: Oncogene 27 Pages: 441-449
  • Peer Reviewed
• [Journal Article] ATM-dependent nudear accumhlation of IKK-α plays an important role in the regulation of p73-mediated apoptosis in response to cisplatin. (2008)
  • Author(s): Yoshida K, Nakagawara A, 他8名、10番目
  • Journal Title: Oncogene 27 Pages: 1183-1188
  • Peer Reviewed
• [Journal Article] Stress via p53 pathway causes apoptosis by mitochondrial Noxaup-regulation in doxorubicin-treated neuroblastoma cells. (2008)
  • Author(s): Kurata K, Nakagawara A, 他4名、5番目
  • Journal Title: Oncogene 27 Pages: 741-754
  • Peer Reviewed
• [Journal Article] Activation of AMP-activated protein kinase induces p53-dependent apoptotic cell death in response to energetic stress. (2008)
  • Author(s): Okoshi R, Nakagawara A, 他8名、9番目
  • Journal Title: J.Biol.Chem 283 Pages: 3979-3987
  • Peer Reviewed
• [Journal Article] A novel HECT-type E3 ubiquitin protein ligase NEDL1 enhances the p53-,mediated apoptptic cell death in its catalytic activity-independent manner. (2008)
  • Author(s): Li Y, Nakagawara A., 他4名、6番目
  • Journal Title: Oncogene (In press)
  • Peer Reviewed
• [Journal Article] Inhibitory role Plk1 in the regulation of p73-dependent apoptpsis through pysical interaction and phsphorylation. (2008)
  • Author(s): Koida N,Nakagawara A., 他8名、10番目
  • Journal Title: J.Biol.Chem. 283 Pages: 8555-8563
  • Peer Reviewed
• [Journal Article] A newly identified dependence receptor UNC5H4 is induced during DNA damage-mediated apoptosis and transcriptional target of tumor suppressor p53. (2008)
  • Author(s): Wang H, Nakagawara A., 他5名、7番目
  • Journal Title: Biochem.Biophys.Res.Commun (In press)
  • Peer Reviewed
• [Journal Article] A novel technique for measuring variations in DNA copy-number:competitive genomic polymerase chain reaction (2007)
  • Author(s): Iwao-Koizumi K, Nakamura Y, Nakagawara A
  • Journal Title: BMC Genomics 8 Pages: 206-206
  • Peer Reviewed
• [Journal Article] NFBD1/MDC1 associates with p53 and regulates its function at the crossroad between cell survival and death in response to DNA damage (2007)
  • Author(s): Nakanishi M, Nakagawara A
  • Journal Title: J.Biol. Chem 282 Pages: 22993-23004
  • Peer Reviewed
• [Journal Article] Stabilization of p73 by nuclear IxB kinase α mediates cisplatin-induced apoptosis (2007)
  • Author(s): Furuya K, Nakagawara
  • Journal Title: J.Biol. Chem 282 Pages: 18365-18378
  • Peer Reviewed
• [Journal Article] DFF45/ICAD restores cisplatin-induced fragmentation but not DNA cleavage in DFF45-deficient neuroblastoma cells (2007)
  • Author(s): Takahashi M, Nakagawara A
  • Journal Title: Oncogene 26 Pages: 5669-5673
  • Peer Reviewed
• [Journal Article] Silencing Ku80 using small interfering RNA enhanced radiation sensitivity in vitro and in vivo (2007)
  • Author(s): Nimura Y, Nakagawara A
  • Journal Title: Int. J. Oncol 30 Pages: 1477-1484
  • Peer Reviewed
• [Journal Article] Puriffication of human primary neuroblastomas by magnetic beads and their in vitro culture (2007)
  • Author(s): Nakanishi H, Nakamura Y, Nakagawara A
  • Journal Title: Oncol. Rep 17 Pages: 1315-1320
  • Peer Reviewed
• [Journal Article] Functional characterization of a new p53 mutant generated by homozygous deletion in a neuroblastoma cell line (2007)
  • Author(s): Nakamura Y, Nakagawara A
  • Journal Title: Biochem Biophys Res Commun 354 Pages: 892-898
  • Peer Reviewed
• [Journal Article] Oxidative stress induces p53-dependent apotosis in hepatoblastoma cell through its nuclear translocation (2007)
  • Author(s): Yamamoto H, Nakagawara A
  • Journal Title: Genes to Cells 12 Pages: 461-471
  • Peer Reviewed
• [Journal Article] Tumor suppressor proteins are differentially affected in human ependymoblastoma and medulloblastoma cells exposed to nerve growth factor (2007)
  • Author(s): Antonelli A, Nakagawara A
  • Journal Title: Cancer Investigation 25 Pages: 94-101
  • Peer Reviewed
• [Journal Article] Relationship of DDX1 and NAG gene amplification/overexpression to the prognosis of patienmts with MYCN-amplified neuroblastoma (2007)
  • Author(s): Kaneko S, Nakamura Y, Nakagawara A
  • Journal Title: J.Cancer Res. Clin. Oncol 133 Pages: 185-192
  • Peer Reviewed
• [Journal Article] Reciprocal expression of CCAAT/enhancer binding proteins α and βin hepatoblastomas and its prognostic significance (2007)
  • Author(s): Tomizawa M, Nakagawara A
  • Journal Title: Oncol. Rep 17 Pages: 341-344
  • Peer Reviewed
• [Journal Article] Marked and independent prognostic signifficance of the CpG island methylator phenotype in neuroblastomas (2007)
  • Author(s): Abe M, Nakagawara A
  • Journal Title: Cancer Lett 247 Pages: 2253-258
  • Peer Reviewed
• [Journal Article] Functional characterization of a new p53 mutant generated by homozygous deletion in a neuroblastoma cell line. (2007)
  • Author(s): Nakamura Y, Nakagawara A., 他4名、6番目
  • Journal Title: Biochem.Biophys.Res.Commun. 354 Pages: 892-898
  • Peer Reviewed
• [Journal Article] DFF45/ICAD restores cisplatin-induced nuclear fragmentation but not DNA cleavage in DFF45-deficient neuroblastoma cells. (2007)
  • Author(s): Takahashi M, Nakagawara A, 他8名、10番目
  • Journal Title: Oncogene 26 Pages: 5669-5673
  • Peer Reviewed
• [Journal Article] Stabilization of p73 by nuclear IκB kinase-α mediates cisplatin-induced apoptosis. (2007)
  • Author(s): Furuya K, Nakagawara A. 他7名、9番目
  • Journal Title: J.Biol.Chem 282 Pages: 18365-18378
  • Peer Reviewed
• [Journal Article] NFBD1/MIDC1 associates with p53 and regulates its function at the crossroad between cell survival and death in response to DNA damage. (2007)
  • Author(s): Nakanishi M, Nakagawara A., 他7名、9番目
  • Journal Title: J.Biol.Chem 282 Pages: 22993-23004
  • Peer Reviewed
• [Presentation] Role of dependence receptors in spontaneous regression of neuroblastoma. (2007)
  • Author(s): Nakagawara A.
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-03