ERalpha and STAT5a cross-talk: interaction through C-terminal portions of the proteins decreases STAT5a phosphorylation, nuclear translocation and DNA-binding.
Cross-talk between ERalpha and STAT5a was demonstrated to mediate through a direct physical association between the two proteins. By GST pull-down assays and functional assays with various constructs of ERalpha and STAT5a, it was shown that the C-termini of these two proteins were mainly responsible for this interaction. Furthermore, the interaction between ERalpha and STAT5a was demonstrated to give rise to functional changes in their signaling events. In cell transfection studies, it was shown that ERalpha activation could attenuate PRLR signaling through STAT5a. This ERalpha-mediated attenuation of PRLR signaling was substantiated by observed decreases in the phosphorylation of JAK2 and STAT5a, reduced translocation of STAT5a into the nucleus, and reduced binding of STAT5a onto a GAS-containing nucleotide. Apart from transfected cells, the interaction between ERalpha and STAT5a could also be observed in established breast cancer cell lines of MCF-7 and T-47D in co-immunoprecipitation studies. However, the functional consequence of the interaction in these cancer cells was very different from the transfected HEK293 cells. ER activation could lead to potentiation of PRLR signaling in MCF-7 cells but not in T-47D cells. Conversely, in both MCF-7 and T-47D cells, PRLR activation could lead to attenuation of ER signaling. These data serve to elucidate the mechanisms underlying the ERalpha-STAT5a cross-talk and in demonstrating that the functional consequence of this cross-talk depends on the precise milieus of the intracellular environment.
Wang
Ying
Y
Department of Biochemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, PR China.
Cheng
Christopher H K
CH
D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D047628:Estrogen Receptor alpha; D005260:Female; D006801:Humans; D051379:Mice; D008894:Milk Proteins; D010766:Phosphorylation; D010957:Plasmids; D011388:Prolactin / Q000494:pharmacology; D020239:Receptor Cross-Talk / Q000502:physiology; D011960:Receptors, Estrogen / Q000502:physiology*; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D025521:Tumor Suppressor Proteins
D017931:DNA Primers; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D008894:Milk Proteins; D011960:Receptors, Estrogen; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D011388:Prolactin