Differential modulation of transcriptional activity of estrogen receptors by direct protein-protein interactions with the T cell factor family of transcription factors.
Two major signaling pathways, those triggered by estrogen (E(2)) and by the Wnt family, interact in the breast to cause growth and differentiation. The estrogen receptors ER(alpha) and ER(beta) are activated by binding E(2) and act as ligand-dependent transcription factors. The effector for the Wnt family is the Tcf family of transcription factors. Both sets of transcription factors recognize discrete but different nucleotide sequences in the promoters of their target genes. By using transient transfections of reporter constructs for the osteopontin and thymidine kinase promoters in rat mammary cells, we show that Tcf-4 antagonizes and Tcf-1 stimulates the effects of activated ER/E(2). For mutants of the former promoter, the stimulatory effects of ER(alpha)/E(2) can be made to be dependent on Tcf-1, and for the latter promoter the effects of the T cell factors (TCFs) are dependent on ER/E(2). Direct interaction between ERs and Tcfs either at the Tcf/ER(alpha)-binding site on the DNA or in the absence of DNA is established by gel retardation assays or by coimmunoprecipitation/biosensor methods, respectively. These results show that the two sets of transcription factors can interact directly, the interaction between ERs and Tcf-4 being antagonistic and that between ERs and Tcf-1 being synergistic on the activity of the promoters employed. Since Tcf-4 is the major Tcf family member in the breast, it is suggested that the antagonistic interaction is normally dominant in vivo in this tissue.
El-Tanani
M
M
Cancer and Polio Research Fund Laboratories, Molecular Medicine Group, School of Biological Sciences, University of Liverpool, Liverpool L69 7ZB, United Kingdom.
Fernig
D G
DG
Barraclough
R
R
Green
C
C
Rudland
P
P
D004268:DNA-Binding Proteins / Q000502:physiology*; D051821:Lymphoid Enhancer-Binding Factor 1; D053495:Osteopontin; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000502:physiology*; D020218:Response Elements; D012795:Sialoglycoproteins / Q000235:genetics; D051822:T Cell Transcription Factor 1; D051820:TCF Transcription Factors; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D011960:Receptors, Estrogen; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D051822:T Cell Transcription Factor 1; D051820:TCF Transcription Factors; C553059:Tcf7l2 protein, rat; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D053495:Osteopontin