1. HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin-proteasome pathway.
- Author
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Wang X, Lu G, Li L, Yi J, Yan K, Wang Y, Zhu B, Kuang J, Lin M, Zhang S, and Shao G
- Subjects
- BRCA1 Protein chemistry, Cell Line, Cell Line, Tumor, HEK293 Cells, Humans, Protein Interaction Maps, Protein Stability, Tumor Suppressor Proteins, Ubiquitination, BRCA1 Protein metabolism, Proteasome Endopeptidase Complex metabolism, Ubiquitin metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
The cellular BRCA1 protein level is essential for its tumor suppression activity and is tightly regulated through multiple mechanisms including ubiquitn-proteasome system. E3 ligases are involved to promote BRCA1 for ubiquitination and degradation. Here, we identified HUWE1/Mule/ARF-BP1 as a novel BRCA1-interacting protein involved in the control of BRCA1 protein level. HUWE1 binds BRCA1 through its N-terminus degron domain. Depletion of HUWE1 by siRNA-mediated interference significantly increases BRCA1 protein levels and prolongs the half-life of BRCA1. Moreover, exogenous expression of HUWE1 promotes BRCA1 degradation through the ubiquitin-proteasome pathway, which could explain an inverse correlation between HUWE1 and BRCA1 levels in MCF10F, MCF7 and MDA-MB-231 breast cancer cells. Consistent with a functional role for HUWE1 in regulating BRCA1-mediated cellular response to DNA damage, depletion of HUWE1 by siRNA confers increased resistance to ionizing radiation and mitomycin. These data indicate that HUWE1 is a critical negative regulator of BRCA1 and suggest a new molecular mechanism for breast cancer pathogenesis., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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