The estrogen receptor (ER) is composed of six major functional domains - the A/B domain as the activation function 1 domain, domain C as the DNA-binding domain, domain D as a hinge domain, and domain E/F as the ligand-dependent transcriptional domains. A novel protein (designated as SRB-RGS) that interacted with domains C and D of ER alpha (ER alpha C/D) repressed the transcriptional activity of ER alpha. In this study, we have examined whether ER alpha C/D releases transcriptional suppression of ER alpha by intrinsic SRB-RGS. The expression vector of ER alpha C/D was transfected to the human cancer cell, KPL-1, which expressed the intrinsic ER. Unexpectedly, transcriptional suppression of ER by ER alpha C/D was observed. COS-7 cells, which have no intrinsic ER, showed a similar suppression of ER alpha by co-transfection of ER alpha and ER alpha C/D. The DNA-binding and the estrogen-binding activities of ER alpha decreased on co-transfection of ER alpha C/D, suggesting a decrease in the receptor protein itself. It is likely that the degradation of ER by co-transfection caused the transcriptional suppression of the ER.