Priority Research Papers:
Modulation of estrogen related receptor alpha activity by the kinesin KIF17
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AM Pramodh Bandara Seneviratne1,2,4, Zeynep Turan2,7, Aurelie Hermant3, Patrick Lecine3,6, William O. Smith2, Jean-Paul Borg3, Fanny Jaulin2,5 and Geri Kreitzer1,2,4
1 Department of Molecular, Cellular & Biomedical Sciences, The City University of New York School of Medicine, New York, NY, USA
2 Department of Cell and Developmental Biology, Weill Medical College, Cornell University, New York, NY, USA
3 Centre de Recherche en Cancérologie de Marseille, Aix Marseille Univ UM105, Institut Paoli-Calmettes, UMR7258 CNRS, U1068 INSERM, Cell Polarity, Cell Signalling and Cancer, Equipe labellisée Ligue Contre le Cancer, Marseille, France
4 The City University of New York School of Medicine, New York, NY, USA
5 Gustave Roussy Institute, Villejuif, France
6 BIOASTER, Tony Garnier, Lyon, France
7 California Institute of Technology, Pasadena, CA, USA
Geri Kreitzer, email:
Keywords: kinesin, estrogen related receptor alpha, transcription, breast cancer, epithelial
Received: August 06, 2015 Accepted: May 12, 2017 Published: May 23, 2017
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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