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Modulation of estrogen related receptor alpha activity by the kinesin KIF17

Seneviratne, A. M. Pramodh Bandara and Turan, Zeynep and Hermant, Aurelie and Lecine, Patrick and Smith, William O. and Borg, Jean-Paul and Jaulin, Fanny and Kreitzer, Geri (2017) Modulation of estrogen related receptor alpha activity by the kinesin KIF17. Oncotarget, 8 (31). pp. 50359-50375. ISSN 1949-2553.

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Estrogen-related receptor alpha (ERR1) is an orphan nuclear receptor that can bind transcriptional co-activators constitutively. ERR1 expression correlates with poor patient outcomes in breast cancer, heightening interest in this nuclear receptor as a therapeutic target. Because ERR1 has no known regulatory ligand, a major challenge in targeting its activity is to find cellular or synthetic modulators of its function. We identified an interaction between ERR1 and KIF17, a kinesin-2 family microtubule motor, in a yeast-2-hybrid screen. We confirmed the interaction using in vitro biochemical assays and determined that binding is mediated by the ERR1 ligand-binding/AF2 domain and the KIF17 C-terminal tail. Expression of KIF17 tail domain in either ER-negative or ER-positive breast cancer epithelial cells attenuated nuclear accumulation of newly synthesized ERR1 and inhibited ERR1 transcriptional activity. Conversely, ERR1 transcriptional activity was elevated significantly in KIF17 knock-out cells. Sequence analysis of the KIF17 tail domain revealed it contains a nuclear receptor box with a conserved LXXLL motif found in transcriptional co-activators. Expression of a 12 amino-acid peptide containing this motif was sufficient to inhibit ERR1 transcriptional activity and cell invasion, while deletion of this region from the KIF17 tail resulted in increased ERR1 activity. Together, these data suggest KIF17 modifies ERR1 function by two possible, non-exclusive mechanisms: (i) by regulating nuclear-cytoplasmic distribution or (ii) by competing with transcriptional co-activators for binding to ERR1. Thus targeting the ERR1-KIF17 interaction has potential as a novel strategy for treating breast cancer.

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Additional Information:© 2017 Seneviratne et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: August 06, 2015; Accepted: May 12, 2017; Published: May 23, 2017. Author contributions: AMPBS designed and performed experiments and wrote the manuscript, ZT prepared reagents and performed experiments, FJ prepared reagents, initiated the yeast-2-hybrid screen and generated expression plasmids encoding yeast-2-hybrid positive clones, AH and PL performed the yeast-2-hybrid screen with JPB, WS produced genome-edited cell lines, GK conceived the project, designed experiments and wrote the manuscript. We thank Jean Marc Vanacker for providing the ERRE-Luc reporter construct and Vivek Mittal for providing MDA-MB-LM2 cells. We also thank Elisa Sanchez for assistance producing ERR3 plasmids. This work was supported by grants to GK from the Department of Defense Breast Cancer Research Program (BC095193, contract W81XWH-10-1-0095), the National Institutes of Health (NIGMS-R01GM087575) and the Irma T. Hirschl Trust. Work in the JPB lab was supported by La Ligue Contre le Cancer (Label Ligue), Canceropôle PACA and Institut Paoli-Calmettes. JPB is a scholar of Institut Universitaire de France.
Funding AgencyGrant Number
Department of Defense Breast Cancer Research ProgramBC095193
Department of Defense Breast Cancer Research ProgramW81XWH-10-1-0095
Irma T. Hirschl TrustUNSPECIFIED
La Ligue Contre le Cancer (Label Ligue)UNSPECIFIED
Institut Paoli-CalmettesUNSPECIFIED
Subject Keywords:kinesin, estrogen related receptor alpha, transcription, breast cancer, epithelial
Issue or Number:31
Record Number:CaltechAUTHORS:20170612-101900571
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:78098
Deposited By: Tony Diaz
Deposited On:12 Jun 2017 18:36
Last Modified:03 Oct 2019 18:05

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