Cross-talk between signal transducer and activator of transcription (Stat5) and thyroid hormone receptor-β1 (TRβ1) signaling pathways

PRL and T-3 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, ie. signal transducer and activator of transcription 5 (Stat5) and thyroid hormone receptor beta 1 (TR beta 1). Liganded TR beta 1 in the presence of its heterodimeric partner, retinoid X receptor gamma (RXR gamma), inhibited the PRL-induced Stat5a- and Stat5b-dependent reporter gene expression by up to 60%. This T-3-inhibitory effect studied on Stat5 activity was partly reversed by overexpression of a TR beta 1 dominant negative variant mutated within its nuclear localization signal (TR2A). We next showed that TR beta 1 and TR2A in the presence of RXR gamma increased and decreased, respectively, Stat5 localization into the nucleus regardless of hormonal stimulation. Thus, our data suggest that TRP1 can be associated with Stat5 in the cytoplasm and may be involved in Stat5 nuclear translocation. In PRL-treated cells overexpressing TR beta 1/RXR gamma, both Stat5 and TR beta 1 were coimmunoprecipitated, indicating physical association of the two transcription factors. In these cells, addition of T-3 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 T-3, vs. PRL alone in TR beta 1/RXR gamma transfected cells. However, antibodies directed against TRP1 lowered Stat5-DNA binding and addition of the deacetylase inhibitor trichostatin A (TSA) relieved T-3, 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 TR beta 1.