Cargando…
RNF4-Dependent Oncogene Activation by Protein Stabilization
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...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125238/ https://www.ncbi.nlm.nih.gov/pubmed/27653698 http://dx.doi.org/10.1016/j.celrep.2016.08.024 |
_version_ | 1782469950118559744 |
---|---|
author | Thomas, Jane J. Abed, Mona Heuberger, Julian Novak, Rostislav Zohar, Yaniv Beltran Lopez, Angela P. Trausch-Azar, Julie S. Ilagan, Ma. Xenia G. Benhamou, David Dittmar, Gunnar Kopan, Raphael Birchmeier, Walter Schwartz, Alan L. Orian, Amir |
author_facet | Thomas, Jane J. Abed, Mona Heuberger, Julian Novak, Rostislav Zohar, Yaniv Beltran Lopez, Angela P. Trausch-Azar, Julie S. Ilagan, Ma. Xenia G. Benhamou, David Dittmar, Gunnar Kopan, Raphael Birchmeier, Walter Schwartz, Alan L. Orian, Amir |
author_sort | Thomas, Jane J. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5125238 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
record_format | MEDLINE/PubMed |
spelling | pubmed-51252382016-11-28 RNF4-Dependent Oncogene Activation by Protein Stabilization Thomas, Jane J. Abed, Mona Heuberger, Julian Novak, Rostislav Zohar, Yaniv Beltran Lopez, Angela P. Trausch-Azar, Julie S. Ilagan, Ma. Xenia G. Benhamou, David Dittmar, Gunnar Kopan, Raphael Birchmeier, Walter Schwartz, Alan L. Orian, Amir Cell Rep Article 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. 2016-09-20 /pmc/articles/PMC5125238/ /pubmed/27653698 http://dx.doi.org/10.1016/j.celrep.2016.08.024 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Thomas, Jane J. Abed, Mona Heuberger, Julian Novak, Rostislav Zohar, Yaniv Beltran Lopez, Angela P. Trausch-Azar, Julie S. Ilagan, Ma. Xenia G. Benhamou, David Dittmar, Gunnar Kopan, Raphael Birchmeier, Walter Schwartz, Alan L. Orian, Amir RNF4-Dependent Oncogene Activation by Protein Stabilization |
title | RNF4-Dependent Oncogene Activation by Protein Stabilization |
title_full | RNF4-Dependent Oncogene Activation by Protein Stabilization |
title_fullStr | RNF4-Dependent Oncogene Activation by Protein Stabilization |
title_full_unstemmed | RNF4-Dependent Oncogene Activation by Protein Stabilization |
title_short | RNF4-Dependent Oncogene Activation by Protein Stabilization |
title_sort | rnf4-dependent oncogene activation by protein stabilization |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125238/ https://www.ncbi.nlm.nih.gov/pubmed/27653698 http://dx.doi.org/10.1016/j.celrep.2016.08.024 |
work_keys_str_mv | AT thomasjanej rnf4dependentoncogeneactivationbyproteinstabilization AT abedmona rnf4dependentoncogeneactivationbyproteinstabilization AT heubergerjulian rnf4dependentoncogeneactivationbyproteinstabilization AT novakrostislav rnf4dependentoncogeneactivationbyproteinstabilization AT zoharyaniv rnf4dependentoncogeneactivationbyproteinstabilization AT beltranlopezangelap rnf4dependentoncogeneactivationbyproteinstabilization AT trauschazarjulies rnf4dependentoncogeneactivationbyproteinstabilization AT ilaganmaxeniag rnf4dependentoncogeneactivationbyproteinstabilization AT benhamoudavid rnf4dependentoncogeneactivationbyproteinstabilization AT dittmargunnar rnf4dependentoncogeneactivationbyproteinstabilization AT kopanraphael rnf4dependentoncogeneactivationbyproteinstabilization AT birchmeierwalter rnf4dependentoncogeneactivationbyproteinstabilization AT schwartzalanl rnf4dependentoncogeneactivationbyproteinstabilization AT orianamir rnf4dependentoncogeneactivationbyproteinstabilization |