RNF4-Dependent Oncogene Activation by Protein Stabilization

Jane J. Thomas, Mona Abed, Julian Heuberger, Rostislav Novak, Yaniv Zohar, Angela P. Beltran Lopez, Julie S. Trausch-Azar, Ma Xenia G. Ilagan, David Benhamou, Gunnar Dittmar, Raphael Kopan, Walter Birchmeier, Alan L. Schwartz, Amir Orian

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish
Pages (from-to)3388-3400
Number of pages13
JournalCell Reports
Volume16
Issue number12
DOIs
StatePublished - Sep 20 2016

Keywords

  • STUbL
  • SUMO
  • gene regulation
  • oncogenes
  • ubiquitin

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