UBR5 Is Coamplified with MYC in Breast Tumors and Encodes an Ubiquitin Ligase That Limits MYC-Dependent Apoptosis
- 1 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 80 (7), 1414-1427
- https://doi.org/10.1158/0008-5472.can-19-1647
Abstract
For maximal oncogenic activity, cellular MYC protein levels need to be tightly controlled so that they do not induce apoptosis. Here, we show how ubiquitin ligase UBR5 functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 ubiquitinates MYC, and its effects on MYC protein stability are independent of FBXW7. Silencing of endogenous UBR5 induced MYC protein expression and regulated MYC target genes. Consistent with the tumor suppressor function of UBR5 (Hyd) in Drosophila, Hyd suppressed dMyc-dependent overgrowth of wing imaginal discs. In contrast, in cancer cells UBR5 suppressed MYC-dependent priming to therapy-induced apoptosis. Of direct cancer relevance, MYC and UBR5 genes were co-amplified in MYC-driven human cancers. Functionally, UBR5 suppressed MYC-mediated apoptosis in p53-mutant breast cancer cells with UBR5/MYC co-amplification. Further, single-cell immunofluorescence analysis demonstrated reciprocal expression of UBR5 and MYC in human basal-type breast cancer tissues. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC activity. In MYC amplified, and p53-mutant breast cancer cells, UBR5 has an important role in suppressing MYC-mediated apoptosis priming and in protection from drug-induced apoptosis.Other Versions
Funding Information
- Sigrid Juselius Foundation (N/A)
- Finnish cancer foundation (n/a)
- EC | European Research Council (AuroMYC)
- Suomen Akatemia (286767 and 312439)
- Foundation Martin Escudero (N/A)
- Maud Kuistila Memorial Foundation (N/A)
- Ella and Georg Enhrooth Foundation (N/A)
This publication has 101 references indexed in Scilit:
- Myc-induced AMPK-phospho p53 pathway activates Bak to sensitize mitochondrial apoptosisProceedings of the National Academy of Sciences of the United States of America, 2013
- Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinomaProceedings of the National Academy of Sciences of the United States of America, 2012
- Pretreatment Mitochondrial Priming Correlates with Clinical Response to Cytotoxic ChemotherapyScience, 2011
- Mammalian hyperplastic discs Homolog EDD Regulates miRNA-Mediated Gene SilencingMolecular Cell, 2011
- The N‐end rule pathway and regulation by proteolysisProtein Science, 2011
- Distinct Thresholds Govern Myc's Biological Output In VivoCancer Cell, 2008
- The E3 ubiquitin ligase EDD is an adverse prognostic factor for serous epithelial ovarian cancer and modulates cisplatin resistance in vitroBritish Journal of Cancer, 2008
- FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiationNature Reviews Cancer, 2008
- Evasion of the p53 tumour surveillance network by tumour-derived MYC mutantsNature, 2005
- Myc suppression of the p21Cip1 Cdk inhibitor influences the outcome of the p53 response to DNA damageNature, 2002