| Research Abstract |
Nuclear receptors (NRs) ware thought to regulate transcription of their target genes in a ligand-dependent way through two types of co-activator complexes : The first includes histone acetyl transferases (HATs), such as CBP/p300, PCAF or the p160 family of proteins, while the second is large multiprotein complexes, called DRIP/TRAP/SMCC without HAT activity. Here we identified a large human (h) multiprotein co-activator complex necessary for activation of transcription by the estrogen receptor a (Erα). This complex contains the GCN5 HAT, the c-Myc interacting protein TRRAP/PAF400, the 30 kDa TATA binding protein (TBP) associated factor (TAF_<11>30), and other subunits, similarly to known TFTC (TBP-free TAF_<11>-containing)-type HAT complexes (hTFTC, hPCAF, hSTAGA and yeast SAGA). Direct and ligand-dependent interactions between Erα, or other NRs, and three LXXLL motifs of TRRAP were identified. In the cells Erα transaction was enhanced by co-expression of TRRAP with GCN5, and the purified GCN5 HAT complex potentiated the transaction function of liganded Erα in vitro. Moreover, expression of anti-sense TRRAP RNA inhibited oestrogen-dependent cell growth of breast cancer cells. Thus, the isolated TFTC-type HAT complex acts as a third class of co-activator complex for NR function.
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