2004 Fiscal Year Final Research Report Summary
The functional role of DAN and p53 family genes in neuroblastoma differentiation induced by BMP.
| Project/Area Number |
15591612
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | Chiba Cancer Center Research Institute |
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Principal Investigator |
NAKAMURA Yohko Chiba Cancer Center Research Institute, Division of Biochemistry, Research Fellow, 生化学研究部, 研究員 (60260254)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Neuroblastoma / BMP2 / p53 / p27^<KIP1> / p73 / DAN |
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| Research Abstract |
Bone morphogenetic proteins(BMPs) are the members of TGF-β superfamily, and have been shown to be involved in neural crest cell differentiation. However, it is still unclear whether BMPs could promote neuronal differentiation or survival in human neuroblastoma cells. We heve found that BMP2 has a potent neurotrophic function in certain neuroblastoma cell lines. BMP receptors (I and II) were expressed in 5 neuroblastoma cell lines that we examined including SH-SY5Y, RTBM1, LA-N-5, SK-N-AS and IMR32. The treatment of neuroblastoma cell lines with 1 nM BMP2 induced a marked phosphorylation of Smad1/5 within 30 min. Among them, RTBM1 and LA-N-5 displayed a growth arrest and a subsequent neuronal differentiation in response to BMP2. In contrast, BMP2 induced a growth arrest in SK-N-AS cells, but did not promote a neuronal differentiation. In RTBM1 cells, BMP2-induced neuronal differentiation was associated with a significant decrease in the expression level of DAN, which is mapped to chromo
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some 1p35 and its gene product acts as an antagonist of BMP. Immunoblot analysis revealed that BMP2 treatment caused a down-regulation of both p53 and p73. On the other hand, cyclin-dependent protein kinase inhibitor p27^<KIP1> was markedly increased in response to BMP2. Considering that BMP signal suppresses the expression of p73 which has an ability to regulate the expression levels of DAN, it is likely that these could exist a feedback mechanism by which BMP is regulated.
Although p53 is rarely mutated in neuroblastoma cells, we found a short form of p53 which is largely expressed in cytoplasm of SK-N-AS cells. The antibody that can recognize the extreme COOH-terminal region of p53 didn't detect p53 in SK-N-AS cells. These results suggest that p53 in SK-N-AS cells lacks a COOH-terminal region including nuclear localization signal(NLS). SH-SY5Y cells carrying a wild-type p53 responded to the cisplatin and underwent apoptosis, which was associated with the induction of p21^<WAF1> and bax. On the other hand, cispatin treatment induced G2/M arrest in SK-N-AS cells. Neither the stabilization of p53 nor induction of bax were detected during the cisplatin-mediated G2/M arrest. However, the expression of p21^<WAF1> were induced in response to cisplatin. Therefore, it is possible that cisplatin-resistant phenotype of SK-N-AS cells is attributed to the aberrant form of p53. Less
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Research Products
(18 results)
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[Journal Article] topors, a p53 and topoisomerase I-binding RING finger protein, is a coactivator of p53 in growth suppression induced by DNA damage.2005
Author(s)
Lin, L., Ozaki, T., Takada, Y., Kageyama, H., Nakamura, Y., et al.
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Journal Title
Oncogene 24
Pages: 3385-3396
Description
「研究成果報告書概要(和文)」より
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[Journal Article] topors, a p53 and topoisomerase I-binding RING finger protein, is a coactivator of p53 in growth suppression induced by DNA damage.2005
Author(s)
Lin L, Ozaki T, Takada Y, Kageyama H, Nakamura Y, Hata A, Zhang JH, Simonds WF, Nakagawara A, Koseki H.
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Journal Title
Oncogene 24
Pages: 3385-3396
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Expression profiling using a tumor-specific cDNA microarray predicts the prognosis of intermediate risk neuroblastomas.2005
Author(s)
Ohira M, Oba S, Nakamura Y, Isogai E, Kaneko S, Nakagawa A, Hirata T, Kubo H, Goto T, Yamada S, Yoshida Y, Fuchioka M, Ishii S, Nakagawara A.
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Journal Title
Cancer Cell. 7
Pages: 337-350
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Reduced inflammatory pain in mice deficient in the differential screening-selected gene aberrative in neuroblastoma2004
Author(s)
Ohtori, S., Isogai, E., Hasue, F., Ozaki, T., Nakamura, Y., et al.
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Journal Title
Mol.Cell.Neurosci. 25
Pages: 504-514
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Low expression of human tubulin tyrosine ligase and suppressed tubulin tyrosination/detyrosination cycle are associated with impaired neuronal differentiation in neuroblastomas with poor prognosis.2004
Author(s)
Kato, C., Miyazaki, K., Nakagawa, A., Ohira, M., Nakamura, Y., et al.
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Journal Title
Int.J.Cancer 112
Pages: 365-375
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Reduced inflammatory pain in mice deficient in the differential screening-selected gene aberrative in neuroblastoma.2004
Author(s)
Ohtori S, Isogai E, Hasue F, Ozaki T, Nakamura Y, Nakagawara A, Koseki H, Yuasa S, Hanaoka E, Shinbo J, Yamamoto T, Chiba H, Yamazaki M, Moriya H, Sakiyama S.
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Journal Title
Mol.Cell.Neurosci. 25
Pages: 504-514
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] 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.2003
Author(s)
Tomioka, N., Kobayashi, H., Kageyama, H., Ohira, M., Nakamura, Y., et al.
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Journal Title
Genes Chromosomes Cancer 36
Pages: 139-150
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Expression profiling and characterization of 4200 genes cloned from primary neuroblastomas : identification of 305 genes differentially expressed between favorable and unfavorable subsets.2003
Author(s)
Ohira, M., Morohashi, A., Inuzuka, H., Shishikura, T., Kawamoto, T., Kageyama, H., Nakamura, Y., et al.
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Journal Title
Oncogene 22
Pages: 5525-5536
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Neuroblastoma oligo-capping cDNA project : toward the understanding of the genesis and biology of neuroblastoma.2003
Author(s)
Ohira M, Morohashi A, Nakamura Y, Isogai E, Furuya K, Hamano S, Machida T, Aoyama M, Fukumura M, Miyazaki K, Suzuki Y, Sugano S, Hirato J, Nakagawara A.
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Journal Title
Cancer Lett. 197
Pages: 63-68
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Expression profiling and characterization of 4200 genes cloned from primary neuroblastomas : identification of 305 genes differentially expressed between favorable and unfavorable subsets.2003
Author(s)
Ohira M, Morohashi A, Inuzuka H, Shishikura T, Kawamoto T, Kageyama H, Nakamura Y, Isogai E, Takayasu H, Sakiyama S, Suzuki Y, Sugano S, Goto T, Sato S., Nakagawara A.
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Journal Title
Oncogene. 22
Pages: 5525-5536
Description
「研究成果報告書概要(欧文)」より
