p73およびΔNp73の安定性によるp53の分子機構と発がん

• Project/Area Number: 15023264
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: 中川原 章 千葉県がんセンター, 生化学研究部, 部長 (50117181)
• Co-Investigator(Kenkyū-buntansha): 尾崎 俊文 千葉県がんセンター, 生化学研究部, 上席研究員 (40260252)
• Project Period (FY): 2003
• Project Status: Completed (Fiscal Year 2003)
• Budget Amount: ¥6,400,000 (Direct Cost: ¥6,400,000); Fiscal Year 2003: ¥6,400,000 (Direct Cost: ¥6,400,000)
• Keywords: p53 / p73 / ユビキチンリガーゼ / NEDL2 / UFD2a / プロテアゾーム

Research Abstract

発がんとがんの進展におけるp73,ΔNp73およびp53の安定化を介した分子制御機構に関し、以下のことを明らかにした。神経芽腫cDNAライブラリーからクローニングした新規HECT型E3ユビキチンリガーゼNEDL2は、そのWWドメインを介してp73のカルボキシ末端に存在するPYモチーフを含む領域と物理的に結合し、p73のポリユビキチン化を促進した。しかし、p73は分解されることなく逆に安定化され、転写因子としての活性が亢進された。NEDL2のp53との結合は見られなかった。一方、神経芽腫細胞株において我々が見いだした1p36領域のホモ欠失領域にマップされたE3/E4ユビキチンリガーゼUFD2aは、p73とSAMドメインを介して特異的に結合したが、それをポリユビキチン化する機能は極めて弱かったものの、p73の蛋白分解を促進した。したがって、UFD2aは主にプロテアゾーム以外の分解機構によってp73の分解を促進している可能性が示された。

Research Products

• [Publications] Miyazaki K, Fujita 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] Hamano 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."NGF and Related Molecules in Health and Disease, Ed. By Luigi Aloe and Laura Calza, Progress in Brain Research, Elsevier Science Publisher. 146. 233-242 (2004)
• [Publications] Tomioka N, Kobayashi H, Nakagawara A. et al.: "Chromosomes that show partial loss or gain in near-diploid tumors coincide with chromosomes that show whole loss or gain in near-triploid tumors : Evidence suggesting the involvement of the same genes in the tumorigenesis of high- and low-risk 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, Takahashi M, Nakagawara A, et al.: "Negative autoregulation of p73 and p53 by ΔNp73 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 hepatocellular 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/ECEL1α 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.: "PPM1D 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, 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, Koseki H, 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)