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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...

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Autores principales: 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
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
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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.
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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
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