title: RNF4-Dependent Oncogene Activation by Protein Stabilization.
abstract: Ubiquitylation regulates signaling pathways critical for cancer development and, in many cases, targets proteins for degradation. Here, we report that ubiquitylation by RNF4 stabilizes otherwise short-lived oncogenic transcription factors, including β-catenin, Myc, c-Jun, and the Notch intracellular-domain (N-ICD) protein. RNF4 enhances the transcriptional activity of these factors, as well as Wnt- and Notch-dependent gene expression. While RNF4 is a SUMO-targeted ubiquitin ligase, protein stabilization requires the substrate's phosphorylation, rather than SUMOylation, and binding to RNF4's arginine-rich motif domain. Stabilization also involves generation of unusual polyubiquitin chains and docking of RNF4 to chromatin. Biologically, RNF4 enhances the tumor phenotype and is essential for cancer cell survival. High levels of RNF4 mRNA correlate with poor survival of a subgroup of breast cancer patients, and RNF4 protein levels are elevated in 30% of human colon adenocarcinomas. Thus, RNF4-dependent ubiquitylation translates transient phosphorylation signal(s) into long-term protein stabilization, resulting in enhanced oncoprotein activation.
authors.affiliation: Rappaport Research Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Jane J
authors.initials: JJ
authors.lastname: Thomas
authors.affiliation: Rappaport Research Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Mona
authors.initials: M
authors.lastname: Abed
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125 Berlin, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Heuberger
authors.affiliation: Rappaport Research Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel; Rambam Medical Center, Haifa 31096, Israel.
authors.forename: Rostislav
authors.initials: R
authors.lastname: Novak
authors.affiliation: Rappaport Research Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel; Rambam Medical Center, Haifa 31096, Israel.
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Zohar
authors.affiliation: Instituto de Biotecnologia, Universidad Nacional de Colombia, Bogota D.C. 11132, Colombia.
authors.forename: Angela P
authors.initials: AP
authors.lastname: Beltran Lopez
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Trausch-Azar
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ma Xenia G
authors.initials: MXG
authors.lastname: Ilagan
authors.affiliation: Rappaport Research Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Benhamou
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125 Berlin, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Dittmar
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Kopan
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125 Berlin, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Birchmeier
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Schwartz
authors.affiliation: Rappaport Research Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel. Electronic address: mdoryan@techunix.technion.ac.il.
authors.forename: Amir
authors.initials: A
authors.lastname: Orian
mesh_terms: D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D009857:Oncogenes / Q000502:physiology*; D055550:Protein Stability; D014157:Transcription Factors / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D009687:Nuclear Proteins; C114070:RNF4 protein, human; D014157:Transcription Factors
keywords: STUbL; SUMO; gene regulation; oncogenes; ubiquitin