Abstract
Estrogen receptor beta (ERbeta) activates transcription by binding to estrogen response elements (EREs) and coactivator proteins that act as bridging proteins between the receptor and the basal transcription machinery. Although the imperfect vitellogenin B1, pS2, and oxytocin (OT) EREs each differ from the consensus vitellogenin A2 ERE sequence by a single base pair, ERbeta activates transcription of reporter plasmids containing A2, pS2, B1, and OT EREs to different extents. To explain how these differences in transactivation might occur, we have examined the interaction of ERbeta with these EREs and monitored recruitment of the coactivators amplified in breast cancer (AIB1) and transcription intermediary factor 2 (TIF2). Protease sensitivity, antibody interaction, and DNA pull-down assays demonstrated that ERbeta undergoes ERE-dependent changes in conformation resulting in differential recruitment of AIB1 and TIF2 to the DNA-bound receptor. Overexpression of TIF2 or AIB1 in transient transfection assays differentially enhanced ERbeta-mediated transcription of reporter plasmids containing the A2, pS2, B1, and OT EREs. Our studies demonstrate that individual ERE sequences induce changes in conformation of the DNA-bound receptor and influence coactivator recruitment. DNA-induced modulation of receptor conformation may contribute to the ability of ERbeta to differentially activate transcription of genes containing divergent ERE sequences.
Highlights
Transcription activation requires the coordinated interaction of multiple transacting factors with DNA recognition sites and other regulatory proteins
To explain how these differences in transactivation might occur, we have examined the interaction of Estrogen receptors (ERs) with these estrogen response elements (EREs) and monitored recruitment of the coactivators amplified in breast cancer (AIB1) and transcription intermediary factor 2 (TIF2)
We have compared the ability of ER to induce transcription of reporter plasmids containing the A2 ERE (GGTCANNNTGACC) [33] and ERE sequences that vary from the consensus ERE sequence
Summary
Transcription activation requires the coordinated interaction of multiple transacting factors with DNA recognition sites and other regulatory proteins. In response to cellular signals, transcription factors bind to specific DNA sequences residing in target genes and interact with numerous regulatory proteins to form an active transcription complex and initiate changes in gene expression. In addition to ligand-induced changes in conformation, there is a growing body of evidence to suggest that DNA sequences can modulate protein conformation This allosteric modulation of protein conformation can dramatically alter gene expression, as has been documented with the POU domain-containing transcription factor Pit-1. Allosteric modulation of nuclear receptor conformation has been implicated in influencing transcription of a number of hormoneresponsive genes (19 –24) Both ER␣ and ER bind to EREs and activate transcription, but ER is typically a less potent activator of reporter plasmids containing the vitellogenin A2 ERE compared with ER␣ [25,26,27,28]. The decreased affinity of ER for the ERE compared with ER␣ could impair its ability to activate
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