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. 2003 Mar 15;370(Pt 3):1087–1095. doi: 10.1042/BJ20020471

Cross-talk between glucocorticoid and retinoic acid signals involving glucocorticoid receptor interaction with the homoeodomain protein Pbx1.

Nanthakumar Subramaniam 1, Javier Campión 1, Ingalill Rafter 1, Sam Okret 1
PMCID: PMC1223238  PMID: 12487626

Abstract

Glucocorticoid (GC) signalling influences the response of the cell to a number of other signals via a mechanism referred to as 'cross-talk'. This cross-talk may act at several levels, including an interaction between the transcription factors involved in the signalling pathways. In the present paper, we demonstrate a novel functional interaction between GC and all- trans -retinoic acid (RA) signalling. We show that, in P19 embryonal carcinoma cells, GCs potentiate RA-induced expression of the murine Hoxb -1 gene through an autoregulatory element, b1-ARE, recognized by the Pbx1 and HOXB1 homoeodomain proteins. The synergistic effect of GC did not involve GC receptor (GR) binding to the b1-ARE, and the GC-GR complex alone was unable to activate transcription via the element. Furthermore, the ability of the GR to transactivate was not required, excluding expression of a GC-induced protein as the mechanism for the GC/RA synergy. Additional transfection experiments showed that the Pbx1/HOXB1 heterodimer was the target for the GC effect. Furthermore, functional dissection of the GR demonstrated that the DNA-binding domain (DBD) of the GR was required for the synergy. A physical interaction between the GR and Pbx1 proteins was demonstrated in vivo by co-immunoprecipitation experiments. These results are compatible with a model in which the GC/RA synergy is mediated by a direct interaction between the GR and Pbx1. On the basis of the ubiquitous expression of both GR and Pbx1, a number of genes regulated by Pbx are likely to be important targets for GC-mediated 'cross-talk'.

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Selected References

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