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

Area of Science:

• Molecular Endocrinology
• Epigenetics
• Cancer Biology

Background:

• Nuclear receptor corepressors (N-CoR) and SMRT form complexes with histone deacetylases (HDACs).
• Estrogen receptor alpha (ER alpha) signaling is crucial for various cellular processes.
• Mutations in ER alpha can lead to aberrant signaling pathways.

Purpose of the Study:

• To investigate the function of a mutant ER alpha (ER alpha-Delta AF2) lacking the C-terminal activation function 2 (AF2) core domain.
• To elucidate the mechanism by which ER alpha-Delta AF2 mediates transcriptional repression.
• To determine the role of cofactors like BRG1, SWI/SNF, N-CoR/SMRT, and HDACs in ER alpha-Delta AF2-mediated repression.

Main Methods:

• Cell-based assays using SW-13 cells (lacking BRG1).
• Analysis of estradiol (E(2))-dependent gene expression.
• Treatment with HDAC inhibitor trichostatin A.
• In vivo association studies of ER alpha-Delta AF2 with SMRT and DNA.

Main Results:

• ER alpha-Delta AF2 directs E(2)-dependent repression and impairs wild-type ER alpha transactivation.
• Repression by ER alpha-Delta AF2 requires coexpressed BRG1 and is abolished by trichostatin A.
• ER alpha-Delta AF2 constitutively associates with SMRT.
• ER alpha-Delta AF2 binds DNA in an E(2)-dependent manner in vivo.

Conclusions:

• ER alpha-Delta AF2 actively perturbs normal E(2) signaling.
• The mechanism involves interactions with SWI/SNF, N-CoR/SMRT, and HDACs.
• Similar mutant receptors found in tumors may contribute to disease progression through these aberrant pathways.