MDM2 regulates estrogen receptor and estrogen responsiveness in breast cancer cells.
Additional Document Info
Murine double minute clone 2 (MDM2) is a multifunctional protein, which modulates nuclear receptor-mediated transactivation. In this study, we show that MDM2 significantly enhanced estrogen receptor (ER) and ER/specificity protein-mediated transactivation in MCF-7 and ZR-75 breast cancer cells. This was demonstrated by both MDM2 overexpression and knockdown experiments by RNA interference. ER interacted with wild-type MDM2 and deletion mutants of MDM2 containing amino acids 1-342 (C-terminal deletion) and 134-490 (N-terminal deletion), but not 134-342. In contrast, only wild-type but not mutant MDM2 enhanced ER-mediated transactivation. Protein-protein interactions in vitro were 17-estradiol (E(2)) independent, whereas fluorescent resonance energy transfer experiments in living cells showed that E(2) enhanced ER-MDM2 interactions. Subsequent RNA interference and mammalian two-hybrid experiments suggested that MDM2 did not directly interact with endogenous coactivators such as the steroid receptor coactivators but played a role in enhancing ER-mediating gene expression and estrogen responsiveness through interactions with ER.