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Differential Subcellular Distribution and Transcriptional Activity of E3, E4, and E3–4 Isoforms of the Rat Estrogen Receptor-

Developpement, Evolution et Plasticité du System Nerveux Institut de Neurobiologie Alfred Fessard Centre Nationale de la Recherche Scientifique 91198 Gif-sur-Yvette cedex, France

E3, E4, and E3–4 are naturally occurring estrogen receptor (ER) isoforms, generated through differential splicing of the ER primary transcript and abundantly expressed in embryonic rat pituitary. Studies in COS cells transfected with full-length ER or its three splice variants fused to green fluorescent protein (GFP), revealed a different subcellular localization for each isoform. In the absence of estradiol, full-length ER-GFP was predominantly nuclear, and E3-GFP and E4-GFP were present both in cytoplasm and nucleus, whereas E3–4-GFP was predominantly cytoplasmic. Upon hormone treatment, a dramatic redistribution of full-length ER-GFP and E3-GFP, from a diffuse to punctate pattern, occurred within the nucleus. In contrast, the distribution of E4-GFP and E3–4-GFP was unaffected. Nuclear fractionation studies showed that full-length ER- and E3 displayed the same hormone-induced ability to tether to nuclear matrix, whereas nuclear E4 appeared to remain loosely associated to functional nuclear constituents. When cotransfected with an estrogen-inducible reporter plasmid (VIT-TK-CAT) in ER-negative (CHO k1) and ER-positive pituitary (GH4 C1) cells, E3–4 exhibited a very weak estrogen-dependent transactivation activity, whereas E3 had an inhibitory effect on full-length ER action. Conversely, E4 displayed estrogen-independent transcriptional activity in ER-negative cells, and in ER-positive cells, enhanced the estrogen-induced gene expression as efficiently as full-length ER. In a gel mobility shift assay, phosphorylated E4 was able to form a specific complex with a consensus ERE, while E3 and E3–4 never did bind by themselves. The observed inhibitory action of E3 on estrogen-dependent transcription would rather involve protein-protein interactions such as formation of heterodimers with full-length ER, as suggested by immunoprecipitation followed by Western blotting. These data suggest that E3 and E4 may play a physiologically relevant role as negative or constitutively positive modulators of transcription, in the developing rat pituitary.

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