Agonist-dependent repression mediated by mutant estrogen receptor alpha that lacks the activation function 2 core domain

Nuclear receptor corepressor (N-CoR) and silencing mediator of retinoid and thyroid hormone receptors (SMRT) form heterogeneous complexes with various histone deacetylases (HDACs). In this report, we found that ER alpha-Delta AF2, a mutant estrogen receptor alpha (ER alpha) deleted for the C-terminal activation function 2 (AF2) core domain, directs estradiol (E(2))-dependent repression and impairs E(2)-induced transactivation by wild type ER alpha. This repression required coexpressed BRG1 in SW-13 cells that lack BRG1, the ATPase constituent of the chromatin-remodeling SWI.SNF complex, and was abolished by HDAC inhibitor trichostatin A. We further demonstrated that ER alpha-Delta AF2 constitutively associates with SMRT but binds DNA in an E(2)-dependent manner in vivo. These results suggest that ER alpha-Delta AF2 and similar mutant receptors recently found associated with certain tumors may actively perturb the normal E(2) signaling via SWI/SNF, N-CoR/SMRT, and HDAC.     

The viral oncogene human papillomavirus E7 deregulates transcriptional silencing by Brm-related gene 1 via molecular interactions

BRG-1, a component of the human SWI/SNF complex, either activates or represses cellular promoters by modulating chromatin structure via the formation of a multiple polypeptide complex. Human papillomavirus E7 binds and destabilizes pRb, resulting in the blockage of G(1) arrest in the cell cycle. We show here that the high-risk human papillomavirus E7 protein group binds BRG-1 and modulates repression of the c-fos promoter mediated by this protein. In addition, both wild-type and Rb binding-defective E7 proteins abolish flat cell formation by BRG-1 in SW13 cells, whereas E7 COOH-terminal mutants do not affect this process. BRG-1-triggered repression of the c-fos promoter is sensitive to trichostatin A. We further establish that BRG-1 contains an activation domain and a trichostatin A-sensitive repression domain. These results collectively suggest that the viral oncogene E7 targets both pRb and BRG-1 via protein-protein interactions, resulting in the deregulation of host cell cycle control.