2004 Fiscal Year Final Research Report Summary
Negative regulation of p53 family protein p73 by transcription factor E2F-1
| Project/Area Number |
15590261
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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 |
General medical chemistry
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| Research Institution | Chiba Cancer Center Research Institute |
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Principal Investigator |
OZAKI Toshinori Chiba Cancer Center Research Institute, Division of Biochemistry, Senior Researcher, 生化学研究部, 上席研究員 (40260252)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAGAWARA Akira Chiba Cancer Center Research Institute, Director, 研究局, 局長 (50117181)
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| Project Period (FY) |
2003 – 2004
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| Keywords | p53 / p73 / E3 ligase / ubiquitin / proteasome / RanBPM / UFD2a / apoptosis |
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| Research Abstract |
We have found for the first time that E2F-1 has an ability to promote the ubiquitin-dependent proteolytic degradation of p73 in COS7 and SAOS-2 cells. Similar results were also obtained in H1299, U2OS, H4 and A549 cells. Deletion analysis revealed that the transactivation function of E2F-1 is required for the degradation of p73. We also demonstrated that a novel HECT-type E3 ubiquitin protein ligase termed NEDL2 interacts with the PY motif of p73, and thereby inducing its ubiquitination. Unexpectedly, NEDL2-mediated ubiquitination of p73 resulted in an incre ase in its half-life, and enhanced its transcriptional activity. These observations strongly suggest that there exists a non-proteolytic regulatory function of the ubiquitination. By using a yeast-based two-hybrid screening, we have identified RanBPM as a binding partner of p73. RanBPM bound to the extreme COOH-terminal region of p73, and increased its stability by inhibiting the ubiquitination levels of p73. It is likely that the COOH-terminal Lys residues could be target(s) for ubiquitination. In addition, we have found that U-box-type E3/E4 ubiquitin protein ligase termed UFD2a induces the proteasome-dependent proteolytic degradation of p73 through the physical interaction with p73. Of note, UFD2a-mediated ubiquitination of p73 was not detected under our experimental conditions. Thus, our present results indicate that p73 is regulated not only by the ubiquitination-dependent degradation pathway but also by the functional interaction with UFD2a in a ubiquitination-independent manner.
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Research Products
(12 results)
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[Journal Article] Identification of protein kinase A catalytic subunit β (PKA-Cβ) as a novel binding partner of p73 and regulation of p73 function.2005
Author(s)
Hanamoto, T., Ozaki, T., Furuya, K., Hosoda, M., Hayashi, S., Nakanishi, M., Yamamoto, H., Kikuchi, H., Todo, S., Nakagawara, A.
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Journal Title
J.Biol.Chem. 280
Pages: 16665-16675
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Protein stability and function of p73 are modulated by a physical interaction with RanBPM in mammalian cultured cells.2005
Author(s)
Kramer, S., Ozaki, T., Miyazaki, K., Kato, C., Hanamoto, T., Nakagawara, A.
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Journal Title
Oncogene 24
Pages: 938-944
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Polo-like kinase 1(Plk1) inhibits p53 function by physical interaction and phosphorylation.2004
Author(s)
Ando, K., Ozaki, T., Yamamoto, H., Furuya, K., Hosoda, M., Hayashi, S., Fukuzawa, M., Nakagawara, A.
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Journal Title
J.Biol.Chem. 279
Pages: 25549-25561
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] A novel HECT-type E3 ubiquitin ligase, NEDL2,stabilizes p73 and enhances its transcriptional activity.2003
Author(s)
Miyazaki, K., Ozaki, T., Kato, C., Hanamoto, T., Fujita, T., Irino, S., Watanabe, K., Nakagawa, T., Nakagawara, A.
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Journal Title
Biochem.Biophys.Res.Commun. 308
Pages: 106-113
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Negative autoregulation of p73 and p53 by DeltaNp73 in regulating differentiation and survival of human neuroblastoma cells.2003
Author(s)
Nakagawa, T., Takahashi, M., Ozaki, T., Watanabe, K., Hayashi, S., Hosoda, M., Todo, S., Nakagawara, A.
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Journal Title
Cancer Lett. 197
Pages: 105-109
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Function of p73,not of p53,is inhibited by the physical interaction with RACK1 and its inhibitory effect is counteracted by pRB.2003
Author(s)
Ozaki, T., Watanabe, K., Nakagawa, T., Miyazaki, K., Takahashi, M., Nakagawara, A.
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Journal Title
Oncogene 22
Pages: 3231-3242
Description
「研究成果報告書概要(欧文)」より
