Document Detail


SCF(Fbxw7/hCdc4) targets cyclin E2 for ubiquitin-dependent proteolysis.
MedLine Citation:
PMID:  19084516     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
E-type cyclins (E1 and E2) regulate the S phase program in the mammalian cell division cycle. Expression of cyclin E1 and E2 is frequently deregulated in a variety of cancer types and a wealth of experimental evidence supports an oncogenic role of these proteins in human tumorigenesis. Although the molecular mechanisms responsible for cyclin E1 deregulation in cancer are well defined, little is known regarding cyclin E2. Here we report that cyclin E2 is targeted for ubiquitin-dependent proteolysis by the ubiquitin ligase SCF(Fbxw7/hCdc4). Ubiquitylation is triggered by phosphorylation of cyclin E2 on residues Thr392 and Ser396, and to a lesser extent Thr74, contained in two consensus Cdc4-phosphodegrons. Furthermore, we found that ectopic expression of cyclin E1 enhances the ubiquitin-dependent proteolysis of cyclin E2 in vivo, suggesting a potential cross-talk in the regulation of E-type cyclin activity. Since SCF(Fbxw7/hCdc4) is functionally inactivated in several human cancer types, alteration of this molecular pathway could contribute to the deregulation of cyclin E2 in tumorigenesis.
Authors:
Kathleen Klotz; Diana Cepeda; Yingmeei Tan; Dahui Sun; Olle Sangfelt; Charles Spruck
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-12-03
Journal Detail:
Title:  Experimental cell research     Volume:  315     ISSN:  1090-2422     ISO Abbreviation:  Exp. Cell Res.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-06-01     Completed Date:  2009-06-16     Revised Date:  2011-05-23    
Medline Journal Info:
Nlm Unique ID:  0373226     Medline TA:  Exp Cell Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1832-9     Citation Subset:  IM    
Affiliation:
Sidney Kimmel Cancer Center, 10905 Road to the Cure, San Diego, CA 92121, USA.
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MeSH Terms
Descriptor/Qualifier:
Binding Sites
Cell Cycle
Cell Cycle Proteins / metabolism*
Cell Line, Tumor
Cyclin E / antagonists & inhibitors,  genetics,  metabolism
Cyclins / chemistry,  genetics,  metabolism*
F-Box Proteins / metabolism*
Hela Cells
Humans
Mutagenesis, Site-Directed
Neoplasms / genetics,  metabolism,  pathology
Oncogene Proteins / antagonists & inhibitors,  genetics,  metabolism
Phosphorylation
RNA Interference
Recombinant Proteins / chemistry,  genetics,  metabolism
Serine / chemistry
Substrate Specificity
Threonine / chemistry
Ubiquitin / metabolism*
Ubiquitin-Protein Ligases / metabolism*
Chemical
Reg. No./Substance:
0/CCNE1 protein, human; 0/CCNE2 protein, human; 0/Cell Cycle Proteins; 0/Cyclin E; 0/Cyclins; 0/F-Box Proteins; 0/Oncogene Proteins; 0/Recombinant Proteins; 0/Ubiquitin; 56-45-1/Serine; 72-19-5/Threonine; EC 6.3.2.19/FBXW7 protein, human; 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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