Receptor-interacting protein 140 binds c-Jun and inhibits estradiol-induced activator protein-1 activity by reversing glucocorticoid receptor-interacting protein 1 effect.
In the presence of estradiol, estrogen receptor-alpha (ERalpha) increases transcription triggered by activator protein-1 (AP-1). We have previously shown that induction is mediated by the direct interaction between c-Jun and ERalpha, which stabilizes a multiprotein complex containing the coactivator GRIP1 (glucocorticoid receptor interacting protein 1). The effect of receptor-interacting protein 140 (RIP140) in this regulation was assessed in the present study. We report that overexpression of RIP140 inhibits estradiol-induced AP-1-dependent transcription in a dose-dependent manner. Inhibition is not affected by trichostatin A, suggesting that histone deacetylase recruitment is not implicated. RIP140, which binds Jun proteins in pull-down assays and in intact cells, as shown by coimmunoprecipitation analysis and a mammalian one-hybrid system, participates in a multiprotein complex containing c-Jun and ERalpha. Moreover, the negative effect of RIP140 on AP-1-mediated transcription is relieved by GRIP1 overexpression and, conversely, RIP140 inhibits the stimulatory effect of GRIP1. The two cofactors compete for binding to c-Jun and ERalpha both in vitro and in intact cells, and GRIP1 interaction with both ERalpha and c-Jun is required for an efficient competition. These overall results suggest that the ratio between RIP140 and GRIP1 could determine, as proposed for hormone response element-mediated responses, the efficacy of estradiol in stimulating transcription of genes under AP-1 control.
Pubmed ID: 12554755 RIS Download
Adaptor Proteins, Signal Transducing | Binding Sites | Binding, Competitive | Cells, Cultured | Dose-Response Relationship, Drug | Enzyme Inhibitors | Estradiol | Estrogen Receptor alpha | Histone Deacetylase Inhibitors | Humans | Hydroxamic Acids | Macromolecular Substances | Multiprotein Complexes | Nuclear Proteins | Nuclear Receptor Coactivator 2 | Proto-Oncogene Proteins c-jun | Receptors, Estrogen | Repressor Proteins | Transcription Factor AP-1 | Transcription Factors