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Progesterone receptor regulates bcl-x expression through distal HREs.
BERTUCCI, P.Y.; BALLARE, C; ALLÓ, M; ROCHA VIEGAS, L.; KORNBLIHTT, A.R.; BEATO, M.; VICENT, G.P.; PECCI, A
Congreso; EMBO Conference Series on Nuclear Receptors: from molecular mechanism to health and disease; 2011
Steroid Receptors (SRs) regulate gene expression by binding to Hormone Responsive Elements (HREs) located within promoter regions of target genes. Upon DNA interaction, SRs modulate the formation of the pre-initiation complex by recruiting histone modifiers and ATP-dependent chromatin remodelers. However, genome wide analyses showed that most HREs are located far from promoters, even in intragenic regions; although the mechanisms involved in hormone transcriptional control through these distal HREs are still not well understood. The synthetic progestin R5020 prevents human breast cancer cells T47D from apoptosis by enhancing the antiapoptotic isoform of human bcl-x (hbcl-x) gene. We found that activated Progesterone Receptor (PR) binds to specific HREs present in hbcl-x located at 3, 45 and 60kb from promoters, at intronic and intergenic regions in the 3´of the gene. These sites directly respond to the activated PR when they are subcloned upstream of a reported vector. However, the kinetic of PR recruitment to these HREs in their endogenous chromatin context differs among sites which display higher PR binding as close to the 3 of the gene they are. Binding of activated PR directly correlates with the recruitment of CBP and GCN5 to the HREs with a concomitant loss of histones H2A, H3 and H4. Inhibition of PolII elongation did not prevent the binding of PR and CBP to HREs. However, after hormone treatment an increase in the PolII occupancy to the 3 of the gene was observed, suggesting a hormonal effect on PolII elongation efficiency.