| Bimodal degradation of MLL by SCFSkp2 and APCCdc20 assures cell cycle execution: a critical regulatory circuit lost in leukemogenic MLL fusions. | |
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MedLine Citation:
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PMID: 17908926 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Human chromosome 11q23 translocations disrupting MLL result in poor prognostic leukemias. It fuses the common MLL N-terminal approximately 1400 amino acids in-frame with >60 different partners without shared characteristics. In addition to the well-characterized activity of MLL in maintaining Hox gene expression, our recent studies established an MLL-E2F axis in orchestrating core cell cycle gene expression including Cyclins. Here, we demonstrate a biphasic expression of MLL conferred by defined windows of degradation mediated by specialized cell cycle E3 ligases. Specifically, SCF(Skp2) and APC(Cdc20) mark MLL for degradation at S phase and late M phase, respectively. Abolished peak expression of MLL incurs corresponding defects in G1/S transition and M-phase progression. Conversely, overexpression of MLL blocks S-phase progression. Remarkably, MLL degradation initiates at its N-terminal approximately 1400 amino acids, and tested prevalent MLL fusions are resistant to degradation. Thus, impaired degradation of MLL fusions likely constitutes the universal mechanism underlying all MLL leukemias. Our data conclude an essential post-translational regulation of MLL by the cell cycle ubiquitin/proteasome system (UPS) assures the temporal necessity of MLL in coordinating cell cycle progression. |
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Authors:
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Han Liu; Emily H-Y Cheng; James J-D Hsieh |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Genes & development Volume: 21 ISSN: 0890-9369 ISO Abbreviation: Genes Dev. Publication Date: 2007 Oct |
Date Detail:
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Created Date: 2007-10-02 Completed Date: 2007-11-27 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 8711660 Medline TA: Genes Dev Country: United States |
Other Details:
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Languages: eng Pagination: 2385-98 Citation Subset: IM |
Affiliation:
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Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Cell Cycle Cell Cycle Proteins / metabolism* Hela Cells Humans Leukemia, Myeloid / etiology Myeloid-Lymphoid Leukemia Protein / genetics, metabolism* Oncogene Proteins, Fusion / genetics, metabolism* Protein Processing, Post-Translational S-Phase Kinase-Associated Proteins / metabolism* Ubiquitin-Protein Ligases / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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CA119008/CA/NCI NIH HHS; CA125562/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cell Cycle Proteins; 0/MLL protein, human; 0/Oncogene Proteins, Fusion; 0/S-Phase Kinase-Associated Proteins; 149025-06-9/Myeloid-Lymphoid Leukemia Protein; 156288-95-8/CDC20 protein, human; EC 6.3.2.19/Ubiquitin-Protein Ligases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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