2004 Fiscal Year Final Research Report Summary
Function of MM-1, a novel c-Myc-binding protein, as a tumor suppressor
| Project/Area Number |
15590053
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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 |
Biological pharmacy
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
TAIRA Takahiro HOKKAIDO UNIVERSITY, Grad.School of Pharma.Sci., Asso.Prof., 大学院・薬学研究科, 助教授 (70197036)
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| Project Period (FY) |
2003 – 2004
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| Keywords | MM-1 / tumor suppressor / c-Myc / ubiquitin / Wnt signal / c-fms / proteasome / transcriptional regulation |
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| Research Abstract |
1).Identification of a novel transrepression pathway of c-Myc and its target gene
We have found that MM-1 bound to TIF1β, a transcriptional corepressor, and that MM-1 recruited a corepressor complex, including HDAC1 and mSin3, to c-Myc, thereby leading to repressing c-Myc transcription activity. To identify target genes to this pathway, a MycER cell line harboring a dominant-negative form of TIF1β, in which the corepressor complex was not recruited to c-Myc, was first established. DNA-microarray method was then applied to identify genes whose expressions were upregulated in this line compared to those in MycER cells. By this system we identified c-fms oncogene as the c-Myc-MM-1 repressed gene. Furthermore, we also identified the Wint-4 gene as a transcriptional repression target of MM-1. In MM-1-knockdown cells, the Wint signal was found to be activated, resulting in activation of c-myc expression.
2).Identification of a novel degradation pathway of c-Myc
We have also identified Elongin B, 26Sproteasome subunits Rpt3 and Rpn12 as MM-1-associated proteins. Since these proteins functions for ubiquitination and degradation of proteins, we then tested a possibility that MM-1 plays a role in c-Myc degradation. The results indicate that MM-1 stimulated c-Myc degradation through the novel E3 ubiquitin ligase complex, including Spk2, Cullin 1, Elongon B, and these phenomena were confirmed to occur in vivo using siRNAs targeting each genes.
These findings indicate that MM-1 is a key protein that negatively regulates c-Myc function and that lost of these functions of MM-1 by mutations leads to tumor formation by c-Myc.
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Research Products
(12 results)
