Forkhead Homologue in Rhabdomyosarcoma Functions as a Bifunctional Nuclear Receptor-interacting Protein with Both Coactivator and Corepressor Functions

Holly Hong Zhao, Rafael E. Herrera, Ester Coronado-Heinsohn, Michael C. Yang, John H. Ludes-Meyers, Karen J. Seybold-Tilson, Zafar Nawaz, Douglas Yee, Frederic G. Barr, Sami G. Diab, Powel H. Brown, Suzanne A.W. Fuqua, C. Kent Osborne

Research output: Contribution to journalArticle

140 Scopus citations

Abstract

In a search for novel transcriptional intermediary factors for the estrogen receptor (ER), we used the ligand-binding domain and hinge region of ER as bait in a yeast two-hybrid screen of a cDNA library derived from tamoxifen-resistant MCF-7 human breast tumors from an in vivo athymic nude mouse model. Here we report the isolation and characterization of the forkhead homologue in rhabdomyosarcoma (FKHR), a recently described member of the hepatocyte nuclear factor 3/forkhead homeotic gene family, as a nuclear hormone receptor (NR) intermediary protein. FKHR interacts with both steroid and nonsteroid NRs, although the effect of ligand on this interaction varies by receptor type. The interaction of FKHR with ER is enhanced by estrogen, whereas its interaction with thyroid hormone receptor and retinoic acid receptor is ligand-independent. In addition, FKHR differentially regulates the transactivation mediated by different NRs. Transient transfection of FKHR into mammalian cells dramatically represses transcription mediated by the ER, glucocorticoid receptor, and progesterone receptor. In contrast, FKHR stimulates rather than represses retinoic acid receptor- and thyroid hormone receptor-mediated transactivation. Most intriguingly, overexpression of FKHR dramatically inhibits the proliferation of ER-dependent MCF-7 breast cancer cells. Therefore, FKHR represents a bifunctional NR intermediary protein that can act as either a coactivator or corepressor, depending on the receptor type.

Original languageEnglish (US)
Pages (from-to)27907-27912
Number of pages6
JournalJournal of Biological Chemistry
Volume276
Issue number30
DOIs
StatePublished - Jul 27 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Zhao, H. H., Herrera, R. E., Coronado-Heinsohn, E., Yang, M. C., Ludes-Meyers, J. H., Seybold-Tilson, K. J., Nawaz, Z., Yee, D., Barr, F. G., Diab, S. G., Brown, P. H., Fuqua, S. A. W., & Osborne, C. K. (2001). Forkhead Homologue in Rhabdomyosarcoma Functions as a Bifunctional Nuclear Receptor-interacting Protein with Both Coactivator and Corepressor Functions. Journal of Biological Chemistry, 276(30), 27907-27912. https://doi.org/10.1074/jbc.M104278200