Transcriptional regulation by a naturally occurring truncated rat estrogenreceptor (ER), truncated ER product-1 (TERP-1)

Truncated estrogen receptor product-1 (TERP-1) is a naturally occurring rat estrogen receptor (ER) variant transcribed from a unique start site and co ntaining a unique 5'-untranslated region fused to exons 5-8 of ER alpha. TE RP-1 is detected only in the pituitary, and TERP-1 mRNA levels are highly r egulated during the estrous cycle, exceeding those of the full-length ER al pha on proestrus. These data suggest that TERP-1 may play a role in estroge n- regulated feedback in the pituitary. We examined the ability of TERP-1 t o modulate gene transcription in transiently transfected ER-negative (Cos-1 ) and ER-positive pituitary (alpha T3 and GH3) cell lines. In Cos-1. cells transiently cotransfected with TERP-1 and either ER alpha or ER beta, low l evels of TERP-1 (ratios of < 1:1 with ER) enhanced transcription of model p romoters containing estrogen response elements by an average of 3- to 4-fol d above that seen with ER alone. At higher concentrations of TERP-1 (> 1:1 with ER) transcription was inhibited. TERP-1 also had a biphasic action on transcription in the alpha T3 and GH3 pituitary cell lines, although the st imulatory action was less pronounced. TERP-1 actions were dependent on liga nd-activated ER as TERP-1 did not bind estradiol in transfected Cos-1 cells or in vitro, and estrogen antagonists prevented the stimulatory effects of TERP-1. Coimmunoprecipitation studies suggest that TERP-1 does not bind wi th high affinity to the full-length ER alpha. However, TERP-1 may compete w ith ER for binding sites of receptor cofactors because steroid receptor coa ctivator-1 (SRC-1) rescued the inhibitory actions of TERP-1. The ability of TERP-1 to both enhance and inhibit ER-dependent promoter activity suggests that TERP-1 may play a physiological role in estrogen feedback in the rat pituitary.