Cooperative Coactivation of Estrogen Receptor α in ZR-75 Human Breast Cancer Cells by SNURF and TATA-binding Protein*

SNURF is a small RING finger protein that binds the zinc finger region of steroid hormone receptors and enhances Sp1- and androgen receptor-mediated transcription in COS and CV-1 cells. In this study, we show that SNURF coactivates both wild-type estrogen receptor α (ERα) (4-fold)- and HE19 (ERα deletion of activation function 1 (AF1)) (210-fold)-mediated activation of an estrogen-responsive element promoter in ZR-75 cells. In mammalian two-hybrid assays in ZR-75 cells SNURF interactions were estrogen (E2)-dependent and were not observed with the antiestrogen ICI 182,780. ERα interacted with multiple regions of SNURF; SNURF interactions with ERα were dependent on AF2, and D538N, E542Q, and D545N mutations in helix 12 abrogated both SNURF-ERα binding and coactivation. Moreover, peptide fusion proteins that inhibit interactions between helix 12 of ERα with LXXLL box-containing proteins also blocked ERα coactivation by SNURF. However, cotransfection of SNURF with prototypical steroid receptor coactivators 1, 2, and 3 that contain LXXLL box motifs did not enhance E2 responsiveness, whereas TATA-binding protein (TBP) and SNURF cooperatively coactivated ERα-mediated transactivation. The results are consistent with a unique model for cooperative coactivation of ERα that requires ligand binding, repositioning of helix 12, recruitment of TBP, and interaction with SNURF, which binds both ERα and TBP.

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