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Molecular Endocrinology 15 (11): 1929-1940
Copyright © 2001 by The Endocrine Society

Cross-Talk Between ERs and Signal Transducer and Activator of Transcription 5 Is E2 Dependent and Involves Two Functionally Separate Mechanisms

Malin Hedengran Faulds, Katarina Pettersson, Jan-Åke Gustafsson and Lars-Arne Haldosén

Department of Medical Nutrition, Karolinska Institute, NOVUM, S-14186 Huddinge, Sweden

Address all correspondence and requests for reprints to: Dr. Lars-Arne Haldosen, Department of Medical Nutrition, Karolinska Institute, NOVUM, S-141 86 Huddinge, Sweden. E-mail: Lars-Arne. Haldosen{at}mednut.ki.se

Steroid hormone receptors and signal transducers and activators of transcription (STAT) factors constitute two distinct families of transcription factors activated by different signaling pathways. In previous reports, cross-talk between STAT5 and several steroid receptors has been demonstrated. We investigated putative cross-talk between ER{alpha} and ERß and STAT5. ER{alpha} and ERß were found to potently repress PRL-induced STAT5 transcriptional activity on a ß-casein promoter construct in a ligand-dependent manner. This down-regulation was found to rely on direct physical interaction between the ERs and STAT5, mediated via the ER DNA-binding domain (DBD). The contact between the ER DBD and STAT5 is highly specific; the interaction is abolished if the ER{alpha} DBD is replaced with the DBD of a closely related steroid receptor. The physical interaction, however, is insufficient to confer the repression of STAT5 activity, which in addition requires the ligand-activated C-terminal part of the ERs, although these domains are not in direct contact with STAT5. Negative cross-talk between ERs and STAT5 is thus mediated via several functionally separated domains of the ERs. Our findings may enhance the understanding of mechanisms of regulation of the different hormonal signaling pathways occurring during different functional events in tissues coexpressing ERs and STAT5.




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