Abstract
The substantial availability of hypoxia-inducible factor 1 (HIF-1) for pathophysiological states, such as malignancies and ischemia, is primarily regulated post-translationally through the ubiquitin proteolytic system. The balance between degradation and stabilization of HIF-1α protein is determined by specific E3 ligases. In our search for new E3 ligases that might affect HIF-1α protein expression, we studied the effects of beta-transducin repeat-containing protein (β-TrCP) on the hypoxic pathway in cancer cells. β-TrCP is overexpressed in many tumors and regulates various cellular processes through mediating the degradation of important targets. Unexpectedly, we found that β-TrCP overexpression increases HIF-1α protein expression level as well as HIF-1 transcriptional activity by stabilizing HIF-1α protein and preventing its ubiquitination and proteasomal degradation in prostate cancer cells. By using a proteomic approach, we succeeded in demonstrating that β-TrCP interferes with the association between HIF-1α and HSP70/CHIP, a HIF-1α established E3 ligase complex. Whereas the E3 ligase activity of β-TrCP is well known, antagonizing another E3 ligase is a new mechanism of action of this important E3. We suggest that destroying or suppressing β-TrCP and thereby interrupting the HIF-1 pathway, could be valuable antitumor therapy.
Original language | English |
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Pages (from-to) | 403-413 |
Number of pages | 11 |
Journal | Prostate |
Volume | 79 |
Issue number | 4 |
DOIs | |
State | Published - 1 Mar 2019 |
Bibliographical note
Funding Information:Ms Esther Eshkol is thanked for editorial assistance. This research was supported by the Israel Science Foundation (ISF) (grant No. 1033/09) and by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF).
Funding Information:
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Israel Science Foundation, Grant number: 1033/09
Publisher Copyright:
© 2018 Wiley Periodicals, Inc.