| Complex regulation of cell-cycle inhibitors by Fbxw7 in mouse embryonic fibroblasts. | |
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MedLine Citation:
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PMID: 20023701 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The F-box protein Fbxw7 (also known as Fbw7, SEL-10, hCdc4 or hAgo) mediates the ubiquitylation and thereby contributes to the degradation of proteins that positively regulate cell cycle. Conditional ablation of Fbxw7 in mouse embryonic fibroblasts (MEFs) induces cell-cycle arrest accompanied by abnormal accumulation of the intracellular domain of Notch1 (NICD1) and c-Myc. However, the molecular mechanisms by which the accumulation of NICD1 and c-Myc induces cell-cycle arrest have remained unclear. We have now examined the expression of cell-cycle inhibitors in Fbxw7-deficient MEFs and found that the abundance of p27(Kip1) and p57(Kip2) is paradoxically decreased. This phenomenon appears to be attributable to the accumulation of NICD1, given that it was recapitulated by overexpression of NICD1 and blocked by ablation of RBP-J. Conversely, the expression of p16(Ink4a) and p19(ARF) was increased in an NICD1-independent manner in Fbxw7-null MEFs. The increased expression of p19(ARF) was recapitulated by overexpression of c-Myc and abolished by ablation of c-Myc, suggesting that the accumulation of c-Myc is primarily responsible for that of p19(ARF). In contrast, the upregulation of p16(Ink4a) appeared to be independent of c-Myc. These results indicate that cell-cycle inhibitors undergo complex regulation by the Fbxw7-mediated proteolytic system. |
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Authors:
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K Masuda; Y Ishikawa; I Onoyama; M Unno; I M de Albor?n; K I Nakayama; K Nakayama |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-12-21 |
Journal Detail:
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Title: Oncogene Volume: 29 ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2010 Mar |
Date Detail:
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Created Date: 2010-03-25 Completed Date: 2010-04-23 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 1798-809 Citation Subset: IM |
Affiliation:
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Department of Developmental Genetics, Center for Translational and Advanced Animal Research, Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai 980-8575, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Cycle / drug effects, physiology* Cyclin-Dependent Kinase Inhibitor p27 / drug effects, genetics Cyclin-Dependent Kinase Inhibitor p57 / drug effects, genetics DNA Primers Down-Regulation / drug effects F-Box Proteins / genetics, pharmacology* Fibroblasts / cytology*, drug effects, physiology* Homeostasis / drug effects Mice Mice, Knockout Proto-Oncogene Proteins c-myc / pharmacology RNA Interference RNA, Messenger / genetics Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects, physiology Ubiquitin-Protein Ligases / deficiency, genetics, pharmacology* Ubiquitination |
| Chemical | |
Reg. No./Substance:
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0/Cdkn1b protein, mouse; 0/Cyclin-Dependent Kinase Inhibitor p57; 0/DNA Primers; 0/F-Box Proteins; 0/Fbxw7 protein, mouse; 0/Proto-Oncogene Proteins c-myc; 0/RNA, Messenger; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; EC 6.3.2.19/Ubiquitin-Protein Ligases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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