دورية أكاديمية
أعرض في EDS

Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase.

التفاصيل البيبلوغرافية
العنوان: Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase.
المؤلفون: Peter S; Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany., Bultinck J; Cytokine Receptor Lab, Department of Biochemistry, Ghent University, Ghent, Belgium., Myant K; CRUK Beatson Institute, Glasgow, UK., Jaenicke LA; Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany., Walz S; Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany., Müller J; Department of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands., Gmachl M; Department Lead Discovery, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Treu M; Department Lead Discovery, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Boehmelt G; Department Lead Discovery, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Ade CP; Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany., Schmitz W; Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany., Wiegering A; Department of General, Visceral, Vascular and Paediatric Surgery, University Hospital Würzburg, Würzburg, Germany., Otto C; Department of General, Visceral, Vascular and Paediatric Surgery, University Hospital Würzburg, Würzburg, Germany., Popov N; Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany., Sansom O; CRUK Beatson Institute, Glasgow, UK., Kraut N; Department Lead Discovery, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Eilers M; Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany martin.eilers@biozentrum.uni-wuerzburg.de.
المصدر: EMBO molecular medicine [EMBO Mol Med] 2014 Dec; Vol. 6 (12), pp. 1525-41.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Wiley-Blackwell Country of Publication: Germany NLM ID: 101487380 Publication Model: Print Cited Medium: Internet ISSN: 1757-4684 (Electronic) Linking ISSN: 17574676 NLM ISO Abbreviation: EMBO Mol Med Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Chichester, West Sussex : Wiley-Blackwell
مواضيع طبية MeSH: Colorectal Neoplasms/*enzymology , Oncogene Protein p55(v-myc)/*antagonists & inhibitors , Oncogene Protein p55(v-myc)/*metabolism , Small Molecule Libraries/*pharmacology , Ubiquitin-Protein Ligases/*antagonists & inhibitors, Animals ; Cell Line, Tumor ; Cell Proliferation ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/physiopathology ; Gene Expression Regulation, Neoplastic ; Humans ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/metabolism ; Mice ; Mice, SCID ; Oncogene Protein p55(v-myc)/genetics ; Protein Binding ; Small Molecule Libraries/administration & dosage ; Transcriptional Activation ; Tumor Suppressor Proteins ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism
مستخلص: Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.
(© 2014 The Authors. Published under the terms of the CC BY 4.0 license.)
التعليقات: Comment in: EMBO Mol Med. 2014 Nov 03;6(12):1509-11. doi: 10.15252/emmm.201404735. (PMID: 25368331)
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معلومات مُعتمدة: 12481 United Kingdom CRUK_ Cancer Research UK
فهرسة مساهمة: Keywords: HUWE1; MIZ1; MYC; colorectal cancer; ubiquitination
المشرفين على المادة: 0 (Kruppel-Like Transcription Factors)
0 (Oncogene Protein p55(v-myc))
0 (Small Molecule Libraries)
0 (Tumor Suppressor Proteins)
0 (ZBTB17 protein, human)
EC 2.3.2.26 (HUWE1 protein, human)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
تواريخ الأحداث: Date Created: 20140926 Date Completed: 20150721 Latest Revision: 20240724
رمز التحديث: 20240725
مُعرف محوري في PubMed: PMC4287973
DOI: 10.15252/emmm.201403927
PMID: 25253726
قاعدة البيانات: MEDLINE
الوصف
تدمد:1757-4684
DOI:10.15252/emmm.201403927