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Molecular and Cellular Biology, October 1999, p. 7106-7122, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Developmental Effects of Ectopic Expression of the Glucocorticoid Receptor DNA Binding Domain Are Alleviated by an Amino Acid Substitution That Interferes with Homeodomain Binding

Jun Ming Wang,1 Gratien G. Préfontaine,2 Madeleine E. Lemieux,1 Louise Pope,1 Marie-Andrée Akimenko,3,* and Robert J. G. Haché1,3,4,*

Department of Medicine,1 Graduate Program in Biochemistry,2 Department of Cellular and Molecular Medicine,3 and Department of Biochemistry, Microbiology, and Immunology,4 The Loeb Health Research Institute at the Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada K1Y 4E9

Received 10 May 1999/Returned for modification 21 June 1999/Accepted 24 June 1999

Steroid hormone receptors are distinguished from other members of the nuclear hormone receptor family through their association with heat shock proteins and immunophilins in the absence of ligands. Heat shock protein association represses steroid receptor DNA binding and protein-protein interactions with other transcription factors and facilitates hormone binding. In this study, we investigated the hormone-dependent interaction between the DNA binding domain (DBD) of the glucocorticoid receptor (GR) and the POU domains of octamer transcription factors 1 and 2 (Oct-1 and Oct-2, respectively). Our results indicate that the GR DBD binds directly, not only to the homeodomains of Oct-1 and Oct-2 but also to the homeodomains of several other homeodomain proteins. As these results suggest that the determinants for binding to the GR DBD are conserved within the homeodomain, we examined whether the ectopic expression of GR DBD peptides affected early embryonic development. The expression of GR DBD peptides in one-cell-stage zebra fish embryos severely affected their development, beginning with a delay in the epibolic movement during the blastula stage and followed by defects in convergence-extension movements during gastrulation, as revealed by the abnormal patterns of expression of several dorsal gene markers. In contrast, embryos injected with mRNA encoding a GR peptide with a point mutation that disrupted homeodomain binding or with mRNA encoding the DBD of the closely related mineralocorticoid receptor, which does not bind octamer factors, developed normally. Moreover, coinjection of mRNA encoding the homeodomain of Oct-2 completely rescued embryos from the effects of the GR DBD. These results highlight the potential of DNA-independent effects of GR in a whole-animal model and suggest that at least some of these effects may result from direct interactions with homeodomain proteins.

* Corresponding author. Mailing address for Marie-Andrée Akimenko: The Loeb Health Research Institute, 725 Parkdale Ave., Ottawa, Ontario, Canada K1Y 4E9. Phone: (613) 761-5142. Fax: (613) 761-5036. E-mail: makimenko{at}lri.ca. Mailing address for Robert J. G. Haché: The Loeb Health Research Institute, 725 Parkdale Ave., Ottawa, Ontario, Canada K1Y 4E9. Phone: (613) 761-5142. Fax: (613) 761-5036. E-mail: rhache{at}lri.ca.

Molecular and Cellular Biology, October 1999, p. 7106-7122, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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Copyright © 1999 by the American Society for Microbiology. All rights reserved.