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Cross-Talk between Signal Transducer and Activator of Transcription (Stat5) and Thyroid Hormone Receptor-ß 1 (TRß1) Signaling Pathways

INSERM Unité 344 (H.F.-Y., R.F., K.P., E.M.) Endocrinologie Moléculaire Faculté de Médecine Necker Paris cedex 15, France 75730
Laboratoire de Physiologie Générale et Comparée (FY.H., D.F., B.D., L.A.) Muséum National d’Histoire Naturelle UMR 8572 CNRS Paris cedex 05, France 75231

PRL and T₃ are involved in antagonistic regulations during various developmental processes in vertebrate species. We have studied cross-talk between transcription factors activated by these signaling pathways, i.e. signal transducer and activator of transcription 5 (Stat5) and thyroid hormone receptor ß1 (TRß1). Liganded TRß1 in the presence of its heterodimeric partner, retinoid X receptor (RXR), inhibited the PRL-induced Stat5a- and Stat5b-dependent reporter gene expression by up to 60%. This T₃-inhibitory effect studied on Stat5 activity was partly reversed by overexpression of a TRß1 dominant negative variant mutated within its nuclear localization signal (TR2A). We next showed that TRß1 and TR2A in the presence of RXR increased and decreased, respectively, Stat5 localization into the nucleus regardless of hormonal stimulation. Thus, our data suggest that TRß1 can be associated with Stat5 in the cytoplasm and may be involved in Stat5 nuclear translocation. In PRL-treated cells overexpressing TRß1/RXR, both Stat5 and TRß1 were coimmunoprecipitated, indicating physical association of the two transcription factors. In these cells, addition of T₃ with ovine (o)PRL decreased the amounts of total and tyrosine-phosphorylated Stat5 in the cytoplasm compared with oPRL-treated cells. In the nucleus, no clear difference was observed on Stat5 DNA-binding after treatment with PRL and T₃ vs. PRL alone in TRß1/RXR transfected cells. However, antibodies directed against TRß1 lowered Stat5-DNA binding and addition of the deacetylase inhibitor trichostatin A (TSA) relieved T₃ inhibition on Stat5 transcriptional activity. Thus, we postulated that the negative cross-talk between TR and Stat5 on target genes could involve histone deacetylase recruitment by liganded TRß1.

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