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Inhibition of nuclear hormone receptor activity by calreticulin

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Abstract

WE have shown that a polypeptide of Mr 60,000 (60K) that shares N-terminal homology with a calcium-binding protein, calreticulin, can bind to an amino-acid sequence motif, KXGFFKR, found in the cytoplasmic domains of all integrin α-subunits1. The homologous amino-acid sequence, KXFFKR (where X is either G, A or V), is also present in the DNA-binding domain of all known members of the steroid hormone receptor family2; amino acids in this sequence make direct contact with nucleotides in their DNA-responsive elements and are crucial for DNA binding3. Here we show that both the 60K protein (p60), purified on a KLGFFKR–Sepharose affinity matrix, and recombinant calreticulin can inhibit the binding of androgen receptor to its hormone-responsive DNA element in a KXFFKR-sequence-specific manner. Calreticulin can also inhibit androgen receptor and retinoic acid receptor transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation. Our results indicate that calreticulin can act as an important modulator of the regulation of gene transcription by nuclear hormone receptors.

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Authors and Affiliations

  1. Division of Cancer Research and Department of Medical Biophysics, University of Toronto, Reichmann Research Building, Sunnybrook Health Science Centre, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada

    Shoukat Dedhar, Chung-Yee Leung Hagesteijn, Huiling Yang, Jorge Filmus & Robert G. Hawley

  2. Department of Cancer Endocrinology, BC Cancer Agency, 600 W 10th Avenue, Vancouver, British Columbia, V5Z 4E6, Canada

    Paul S. Rennie, Nicholas Bruchovsky & Helen Cheng

  3. Division of Endocrine Research and Department of Molecular and Medical Genetics, University of Toronto, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada

    Mary Shago & Vincent Giguère

  4. Department of Physiology, University of Manitoba, Winnipeg, Manitoba, R3E OW3, Canada

    Robert J. Matusik

Authors
  1. Shoukat Dedhar
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  2. Paul S. Rennie
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  3. Mary Shago
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  4. Chung-Yee Leung Hagesteijn
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  5. Huiling Yang
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  6. Jorge Filmus
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  7. Robert G. Hawley
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  8. Nicholas Bruchovsky
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  9. Helen Cheng
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  10. Robert J. Matusik
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  11. Vincent Giguère
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Dedhar, S., Rennie, P., Shago, M. et al. Inhibition of nuclear hormone receptor activity by calreticulin. Nature 367, 480–483 (1994). https://doi.org/10.1038/367480a0

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  • DOI: https://doi.org/10.1038/367480a0

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