title: PP2A-B55β antagonizes cyclin E1 proteolysis and promotes its dysregulation in cancer.
abstract: Cyclin E1 regulates the initiation of S-phase in cellular division. However, in many cancers, cyclin E1 is aberrantly overexpressed and this molecular phenotype correlates with increased tumor aggressiveness and poor patient survival. The molecular cause(s) of cyclin E1 abnormalities in cancers is poorly understood. Here, we show that cyclin E1 overexpression in cancer is promoted by dysregulation of the protein phosphatase PP2A-B55β. PP2A-B55β targets the N- and C-terminal phosphodegrons of cyclin E1 for dephosphorylation, thus protecting it from degradation mediated by the SCF(Fbxw7) ubiquitin ligase. Augmented B55β expression stabilizes cyclin E1 and promotes its overexpression in cancer-derived cell lines and breast tumors. Conversely, B55β ablation enforces the degradation of cyclin E1 and inhibits cancer cell proliferation in vitro and tumor formation in vivo. Therefore, PP2A-B55β promotes cyclin E1 overexpression by antagonizing its degradation and its inhibition could represent a therapeutic mechanism for abrogating cyclin E1 function in cancers.
authors: Authors' Affiliations: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California; and Department of Gynaecological Oncology, University College London, London, United Kingdom.
authors: Yingmeei
authors: Y
authors: Tan
authors: Dahui
authors: D
authors: Sun
authors: Weijian
authors: W
authors: Jiang
authors: Kathleen
authors: K
authors: Klotz-Noack
authors: Ajay A
authors: AA
authors: Vashisht
authors: James
authors: J
authors: Wohlschlegel
authors: Martin
authors: M
authors: Widschwendter
authors: Charles
authors: C
authors: Spruck
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019927:Cyclin E / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000378:metabolism*; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000502:physiology*; D054875:Ubiquitination
chemical_list: C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins; D054648:Protein Phosphatase 2