RING finger protein 31 promotes p53 degradation in breast cancer cells

J Zhu; C Zhao; T Zhuang; P Jonsson; I Sinha; C Williams; S Strömblad; K Dahlman-Wright

doi:10.1038/onc.2015.260

RING finger protein 31 promotes p53 degradation in breast cancer cells

Oncogene. 2016 Apr 14;35(15):1955-64. doi: 10.1038/onc.2015.260. Epub 2015 Jul 6.

Authors

J Zhu¹, C Zhao¹, T Zhuang¹, P Jonsson², I Sinha¹, C Williams^{2

3}, S Strömblad¹, K Dahlman-Wright^{1

4}

Affiliations

¹ Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
² Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
³ SciLifeLab, Department of Proteomics and Nanotechnology, The Royal Institute of Technology-KTH, Solna, Sweden.
⁴ SciLifeLab, Science for Life Laboratory, Solna, Sweden.

Abstract

The atypical E3 ubiquitin ligase RNF31 is highly expressed in human breast cancer, the most frequent neoplastic lethality among women. Here, RNF31 depletion in breast cancer cells in combination with global gene expression profiling revealed p53 (TP53) signaling as a potential RNF31 target. Interestingly, RNF31 decreased p53 stability, whereas depletion of RNF31 in breast cancer cells caused cell cycle arrest and cisplatin-induced apoptosis in a p53-dependent manner. Furthermore, RNF31 associated with the p53/MDM2 complex and facilitated p53 polyubiquitination and degradation by stabilizing MDM2, suggesting a molecular mechanism by which RNF31 regulates cell death. Analysis of publically available clinical data sets displayed a negative correlation between RNF31 and p53 target genes, including IGFBP3 and BTG1, consistent with RNF31 regulating p53 function in vivo as well. Together, our findings suggest RNF31 as a potential therapeutic target to restore p53 function in breast cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / metabolism
Adenocarcinoma / pathology*
Apoptosis / drug effects
Breast Neoplasms / metabolism
Breast Neoplasms / pathology*
Cell Division
Cell Line, Tumor
Cisplatin / pharmacology
Female
G1 Phase
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
Neoplasm Proteins / genetics
Neoplasm Proteins / physiology*
Proteasome Endopeptidase Complex / metabolism
Protein Processing, Post-Translational
Protein Stability
Proteolysis
Proto-Oncogene Proteins c-mdm2 / physiology
RNA Interference
RNA, Small Interfering / genetics
Transfection
Tumor Suppressor Protein p53 / metabolism*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / physiology*
Ubiquitination

Substances

Neoplasm Proteins
RNA, Small Interfering
TP53 protein, human
Tumor Suppressor Protein p53
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
RNF31 protein, human
Ubiquitin-Protein Ligases
Proteasome Endopeptidase Complex
Cisplatin