title: COP1 and GSK3β cooperate to promote c-Jun degradation and inhibit breast cancer cell tumorigenesis.
abstract: High abundance of c-Jun is detected in invasive breast cancer cells and aggressive breast tumor malignancies. Here, we demonstrate that a major cause of high c-Jun abundance in invasive breast cancer cells is prolonged c-Jun protein stability owing to poor poly-ubiquitination of c-Jun. Among the known c-Jun-targeting E3 ligases, we identified constitutive photomorphogenesis protein 1 (COP1) as an E3 ligase responsible for c-Jun degradation in less invasive breast cancer cells because depletion of COP1 reduced c-Jun poly-ubiquitination leading to the stabilization of c-Jun protein. In a panel of breast cancer cell lines, we observed an inverse association between the levels of COP1 and c-Jun. However, overexpressing COP1 alone was unable to decrease c-Jun level in invasive breast cancer cells, indicating that efficient c-Jun protein degradation necessitates an additional event. Indeed, we found that glycogen synthase kinase 3 (GSK3) inhibitors elevated c-Jun abundance in less invasive breast cancer cells and that GSK3β nonphosphorylable c-Jun-T239A mutant displayed greater protein stability and poorer poly-ubiquitination compared to the wild-type c-Jun. The ability of simultaneously enforced expression of COP1 and constitutively active GSK3β to decrease c-Jun abundance in invasive breast cancer cells allowed us to conclude that c-Jun is negatively regulated through the coordinated action of COP1 and GSK3β. Importantly, co-expressing COP1 and active GSK3β blocked in vitro cell growth/migration and in vivo metastasis of invasive breast cancer cells. Gene expression profiling of breast tumor specimens further revealed that higher COP1 expression correlated with better recurrence-free survival. Our study supports the notion that COP1 is a suppressor of breast cancer progression.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China ; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA.
authors.forename: Jing
authors.initials: J
authors.lastname: Shao
authors.forename: Yong
authors.initials: Y
authors.lastname: Teng
authors.forename: Ravi
authors.initials: R
authors.lastname: Padia
authors.forename: Sungguan
authors.initials: S
authors.lastname: Hong
authors.forename: Hyangsoon
authors.initials: H
authors.lastname: Noh
authors.forename: Xiayang
authors.initials: X
authors.lastname: Xie
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Mumm
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.forename: Han-Fei
authors.initials: HF
authors.lastname: Ding
authors.forename: John
authors.initials: J
authors.lastname: Cowell
authors.forename: Jaejik
authors.initials: J
authors.lastname: Kim
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D015027:Zebrafish
chemical_list: D034741:RNA, Small Interfering; C471981:COP1 protein, human; D044767:Ubiquitin-Protein Ligases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3
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