title: Both SCF(Cdc4alpha) and SCF(Cdc4gamma) are required for cyclin E turnover in cell lines that do not overexpress cyclin E.
abstract: The ubiquitin-mediated turnover of cyclin E is regulated by phosphorylation and the activity of the ubiquitin ligase SCF(Cdc4) (also known as SCF(Fbw7)). In 293A cells, SCF complexes containing two different Cdc4 isoforms, alpha and gamma, are required for efficient cyclin E ubiquitylation. Whereas SCF(Cdc4gamma) ubiquitylates cyclin E directly, SCF(Cdc4alpha) serves as a cofactor for Pin1-mediated prolyl isomerization of the cyclin E phosphodegron, essential to potentiate ubiquitylation. In the current study, we show that the requirement for both Cdc4alpha and gamma is general, except in cell lines where cyclin E is expressed at an elevated level. Under these circumstances, Cdc4alpha is sufficient for cyclin E turnover. Furthermore, the requirement for Cdc4gamma can be bypassed by ectopic overexpression of cyclin E.
authors.affiliation: Cancer Center Karolinska, Karolinska Sjukhuset, Department of Oncology/Pathology, Stockholm, Sweden. olle.sangfelt@ki.se
authors.forename: Olle
authors.initials: O
authors.lastname: Sangfelt
authors.forename: Diana
authors.initials: D
authors.lastname: Cepeda
authors.forename: Alena
authors.initials: A
authors.lastname: Malyukova
authors.forename: Frank
authors.initials: F
authors.lastname: van Drogen
authors.forename: Steven I
authors.initials: SI
authors.lastname: Reed
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D044783:F-Box Proteins / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005455:Fluorescent Antibody Technique; D006801:Humans; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D019927:Cyclin E; D017931:DNA Primers; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D020033:Protein Isoforms; D044767:Ubiquitin-Protein Ligases