2003 Fiscal Year Annual Research Report

神経芽腫の発生と多剤耐性獲得におけるp53ファミリー遺伝子の役割とその克服

Research Project

Project/Area Number	15390535
Research Institution	Chiba Cancer Center (Research Institute)
Principal Investigator	中川原章千葉県がんセンター(研究所), 生化学研究部, 部長 (50117181)
Co-Investigator(Kenkyū-buntansha)	市川美紀(大平美紀) 千葉県がんセンター(研究所), 生化学研究部, 研究員 (20311384) 尾崎俊文千葉県がんセンター(研究所), 生化学研究部, 上席研究員 (40260252)
Keywords	p53 / p73 / ΔNp73 / 多剤耐性 / BMP2 / シスプラチン耐性 / BMP2
Research Abstract	神経芽腫の発生と多剤耐性獲得におけるp53ファミリー遺伝子の役割に関し、以下の知見を得た。 (1)複数の神経芽腫細胞株をBMP2で処理したところ、2株において神経分化が誘導され、それに伴ってp53とp73がともに蛋白質レベルで発現が低下した。一方、レチノイン酸処理では、分化誘導された細胞ではp53の発現が低下したものの、p73は細胞死が誘導された細胞でのみその蛋白質の発現が見られた。 (2)神経芽腫細胞株をシスプラチン処理すると、p53,p73,ΔNp73すべてが発現誘導された。しかし、p53は半量以上が細胞質に存在し、実際の誘導された量は他のがん細胞に比べ低かった。ΔNp73の誘導は主にp73によるものと考えられた。 (3)シスプラチン耐性細胞株において、p53ファミリー遺伝子と耐性獲得の関係について解析した。その結果、その耐性株には恒常的にp73の発現が見られ、ターゲット遺伝子であるMdm2の誘導を介してp53を分解・抑制することにより耐性を獲得している可能性が示唆された。

Research Products
(19 results)

All Other

All Publications (19 results)

[Publications] Miyazaki K, Ozaki T, Nakagawara A., et al.: "NEDL1, a novel E3 ubiquitin-protein isopeptide ligase for Dishevelled-1, targets mutant superoxide dismutase-1."J.Biol.Chem.. (in press).
[Publications] Hamao S, Ohira M, Nakagawara A., et al.: "Identification of Novel Human Neuronal Leucine-Rich Repeat (hNLRR) Family Genes and Inverse Association of Expression of Nbla10449/hNLRR-1 and Nbla10677/hNLRR-3 with the Prognosis of Primary Neuroblastomas."Int.J.Oncol.. (in press).
[Publications] Wang YQ, Seimiya M, Nakagawara A, et al.: "Elevated expression of DNA polymerase k in human lung cancer is associated with p53 inactivation : negative regulation of POLK promoter activity by p53."Int.J.Oncol.. (in press).
[Publications] Nakagawara A, Ohira M.: "Comprehensive genomics linking between neural development and cancer : Neuroblastoma as a model. In Special Issue : Neural development and cancer."Cancer Lett.. (in press).
[Publications] Nakagawara A.: "Neural crest development and neuroblastoma : the genetic and biological link. In NGF and Related Molecules in Health and Disease, Ed."Progress in Brain Research. 146. 233-242 (2004)
[Publications] Tomioka N, Ohira M, Nakagawara A, et al.: "Chromosomes that show partial loss or gain in near-diploid tumors coincide with chromosome that show whole loss or gain in near-triploid tumor : Evidence suggesting the involvement of the same genes in the tumorigenesis of high-and low-neuroblastomas."Genes Chromosomes Cancer. 36. 139-150 (2004)
[Publications] Okamoto Y, Ozaki T, Nakagawara A., et al.: "UbcH10 is the cancer-related E2 ubiquitin conjugating enzyme."Cancer Res.. 63. 4167-4173 (2003)
[Publications] Ikematsu S, Nakagawara A, Nakamura Y, et al.: "Correlation of elevated level of serum midkine with poor prognostic factors of human neuroblastomas."Br.J.Cancer. 88. 1522-1526 (2003)
[Publications] Nakagawa T, Ozaki T, Todo S, Nakagawara A., et al.: "Negative autoregulation of p73 and p53 by _Np73 in regulating differentiation and survival of human neuroblastoma cells."Cancer Lett.. 197. 105-109 (2003)
[Publications] Ohira M, Morohashi A, Nakagawara A., et al.: "Neuroblastoma Oligo-capping cDNA Project : Toward the Understanding of the Genesis and Biology of Neuroblastoma."Cancer Lett.. 197. 63-68 (2003)
[Publications] Ohira M, Morohashi A, Nakagawara A., et al.: "Expression profiling and characterization of 4,200 genes cloned from primary neuroblastomas : Identification of 305 genes differentially expressed between favorable and unfavorable subsets."Oncogene. 22. 5525-5536 (2003)
[Publications] Miyazaki K, Ozaki T, Nakagawara A., et al.: "A novel HECT-type E3 ubiquitin ligase, NEDL2, stabilizes p73 and enhances its transcriptional activity."Biochem.Biophys.Res.Commun.. 308. 106-113 (2003)
[Publications] Tomizawa M, Watanabe K, Nakagawara A., et al.: "Down-regulated expression of the CCAAT/enhancer binding protein a and b genes in human hapatocellular carcinoma : a possible prognostic marker."Anticancer Res.. 23. 351-354 (2003)
[Publications] Kawamoto T, Ohira M, Nakagawara A., et al.: "High expression of the novel endothelin-converting enzyme genes, Nbla03145/ECEL1 and β, is associated with favorable prognosis in human neuroblastomas."Int.J.Oncol.. 22. 815-822 (2003)
[Publications] Saito-Ohara F, Imoto I, Nakagawara A, et al.: "PPMID is a potential target for 17q gain in neuroblastoma."Cancer Res.. 63. 1876-1883 (2003)
[Publications] Sakiyama S, Yu L, Nakagawara A, et al.: "Utilization of the promoter region of the midkine gene as a tool to drive therapeutic genes in a tumor specific manner."Advan.Enzyme Regul.. 43. 57-66 (2003)
[Publications] Carninci P, Waki K, Shiraki T, Nakagawara A, et al.: "Targeting a complex transcriptome : The construction of the mouse full-length cDNA encyclopedia."Genome Res.. 13. 1273-1289 (2003)
[Publications] Ozaki T, Watanabe K, Nakagawara A, et al.: "Function of p73, not of p53, is inhibited by the physical interaction with RACK1 and its inhibitory effect is counteracted by pRB."Oncogene. 22. 3231-3242 (2003)
[Publications] Nakamura Y, Ozaki T, Nakagawara A, et al.: "Accumulation of p27^<KIP1> is associated with BMP2-mediated growth arrest and neuronal differentiation of human neuroblastoma-derived cell lines."Biochem.Biophys.Res.Commun.. 307. 206-213 (2003)

2003 Fiscal Year Annual Research Report

神経芽腫の発生と多剤耐性獲得におけるp53ファミリー遺伝子の役割とその克服

Principal Investigator

中川原 章 千葉県がんセンター(研究所), 生化学研究部, 部長 (50117181)

Research Products

[Publications] Miyazaki K, Ozaki T, Nakagawara A., et al.: "NEDL1, a novel E3 ubiquitin-protein isopeptide ligase for Dishevelled-1, targets mutant superoxide dismutase-1."J.Biol.Chem.. (in press).

[Publications] Hamao S, Ohira M, Nakagawara A., et al.: "Identification of Novel Human Neuronal Leucine-Rich Repeat (hNLRR) Family Genes and Inverse Association of Expression of Nbla10449/hNLRR-1 and Nbla10677/hNLRR-3 with the Prognosis of Primary Neuroblastomas."Int.J.Oncol.. (in press).

[Publications] Wang YQ, Seimiya M, Nakagawara A, et al.: "Elevated expression of DNA polymerase k in human lung cancer is associated with p53 inactivation : negative regulation of POLK promoter activity by p53."Int.J.Oncol.. (in press).

[Publications] Nakagawara A, Ohira M.: "Comprehensive genomics linking between neural development and cancer : Neuroblastoma as a model. In Special Issue : Neural development and cancer."Cancer Lett.. (in press).

[Publications] Nakagawara A.: "Neural crest development and neuroblastoma : the genetic and biological link. In NGF and Related Molecules in Health and Disease, Ed."Progress in Brain Research. 146. 233-242 (2004)

[Publications] Okamoto Y, Ozaki T, Nakagawara A., et al.: "UbcH10 is the cancer-related E2 ubiquitin conjugating enzyme."Cancer Res.. 63. 4167-4173 (2003)

[Publications] Ikematsu S, Nakagawara A, Nakamura Y, et al.: "Correlation of elevated level of serum midkine with poor prognostic factors of human neuroblastomas."Br.J.Cancer. 88. 1522-1526 (2003)

[Publications] Nakagawa T, Ozaki T, Todo S, Nakagawara A., et al.: "Negative autoregulation of p73 and p53 by _Np73 in regulating differentiation and survival of human neuroblastoma cells."Cancer Lett.. 197. 105-109 (2003)

[Publications] Ohira M, Morohashi A, Nakagawara A., et al.: "Neuroblastoma Oligo-capping cDNA Project : Toward the Understanding of the Genesis and Biology of Neuroblastoma."Cancer Lett.. 197. 63-68 (2003)

[Publications] Ohira M, Morohashi A, Nakagawara A., et al.: "Expression profiling and characterization of 4,200 genes cloned from primary neuroblastomas : Identification of 305 genes differentially expressed between favorable and unfavorable subsets."Oncogene. 22. 5525-5536 (2003)

[Publications] Miyazaki K, Ozaki T, Nakagawara A., et al.: "A novel HECT-type E3 ubiquitin ligase, NEDL2, stabilizes p73 and enhances its transcriptional activity."Biochem.Biophys.Res.Commun.. 308. 106-113 (2003)

[Publications] Tomizawa M, Watanabe K, Nakagawara A., et al.: "Down-regulated expression of the CCAAT/enhancer binding protein a and b genes in human hapatocellular carcinoma : a possible prognostic marker."Anticancer Res.. 23. 351-354 (2003)

[Publications] Kawamoto T, Ohira M, Nakagawara A., et al.: "High expression of the novel endothelin-converting enzyme genes, Nbla03145/ECEL1 and β, is associated with favorable prognosis in human neuroblastomas."Int.J.Oncol.. 22. 815-822 (2003)

[Publications] Saito-Ohara F, Imoto I, Nakagawara A, et al.: "PPMID is a potential target for 17q gain in neuroblastoma."Cancer Res.. 63. 1876-1883 (2003)

[Publications] Sakiyama S, Yu L, Nakagawara A, et al.: "Utilization of the promoter region of the midkine gene as a tool to drive therapeutic genes in a tumor specific manner."Advan.Enzyme Regul.. 43. 57-66 (2003)

[Publications] Carninci P, Waki K, Shiraki T, Nakagawara A, et al.: "Targeting a complex transcriptome : The construction of the mouse full-length cDNA encyclopedia."Genome Res.. 13. 1273-1289 (2003)

[Publications] Ozaki T, Watanabe K, Nakagawara A, et al.: "Function of p73, not of p53, is inhibited by the physical interaction with RACK1 and its inhibitory effect is counteracted by pRB."Oncogene. 22. 3231-3242 (2003)

[Publications] Nakamura Y, Ozaki T, Nakagawara A, et al.: "Accumulation of p27^<KIP1> is associated with BMP2-mediated growth arrest and neuronal differentiation of human neuroblastoma-derived cell lines."Biochem.Biophys.Res.Commun.. 307. 206-213 (2003)

中川原章千葉県がんセンター(研究所), 生化学研究部, 部長 (50117181)