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RNF4-Dependent Oncogene Activation by Protein Stabilization

Jane J Thomas1, Mona Abed1, Julian Heuberger2

  • 1Rappaport Research Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.

Cell Reports
|September 23, 2016
PubMed

Insights

RNF4 ubiquitylation stabilizes key cancer-driving transcription factors, enhancing their activity and promoting tumor growth. This mechanism is crucial for cancer cell survival and linked to poor patient outcomes.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Ubiquitin Signaling

Background:

  • Ubiquitylation is a key regulator of signaling pathways in cancer, often targeting proteins for degradation.
  • Oncogenic transcription factors are typically short-lived, tightly controlling their activity.

Purpose of the Study:

  • To investigate the role of RNF4 in regulating oncogenic transcription factors.
  • To elucidate the mechanism by which RNF4 influences protein stability and transcriptional activity.

Main Methods:

  • Investigated ubiquitylation by RNF4 on specific oncogenic transcription factors (β-catenin, Myc, c-Jun, N-ICD).
  • Analyzed the impact of RNF4 on transcriptional activity and gene expression (Wnt, Notch pathways).
  • Examined the molecular requirements for RNF4-mediated stabilization, including phosphorylation, SUMOylation, and RNF4 domains.

Main Results:

  • RNF4 ubiquitylation stabilizes short-lived oncogenic transcription factors, enhancing their transcriptional activity.
  • Stabilization depends on substrate phosphorylation and RNF4 binding, not SUMOylation, and involves unique polyubiquitin chains and chromatin docking.
  • RNF4 promotes tumor phenotype and cancer cell survival, with elevated RNF4 correlating with poor patient survival and increased incidence in colon adenocarcinomas.

Conclusions:

  • RNF4-dependent ubiquitylation converts transient phosphorylation signals into sustained oncoprotein activation by stabilizing key transcription factors.
  • RNF4 represents a potential therapeutic target in cancers characterized by elevated RNF4 levels or activity.
Keywords:
STUbLSUMOgene regulationoncogenesubiquitin

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