Cross-talk between glucocorticoid and retinoic acid signals involving glucocorticoid receptor interaction with the homoeodomain protein Pbx1.
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'.
Subramaniam
Nanthakumar
N
Department of Medical Nutrition, Karolinska Institutet, Huddinge University Hospital, Novum, SE-141 86 Huddinge, Sweden.
Campión
Javier
J
Rafter
Ingalill
I
Okret
Sam
S
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000378:metabolism*; D006727:Hormone Antagonists / Q000378:metabolism; D051379:Mice; D015735:Mifepristone / Q000378:metabolism; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism*
D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D006727:Hormone Antagonists; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D011965:Receptors, Glucocorticoid; C083400:PBX1 protein, human; D015735:Mifepristone; D014212:Tretinoin