MICoA, a Novel Metastasis-associated Protein 1 (MTA1) Interacting Protein Coactivator, Regulates Estrogen Receptor-α Transactivation Functions

Sandip K Mishra,Abhijit Mazumdar,Ratna K Vadlamudi,Feng Li,Rui-An Wang,Wei Yu,V Craig Jordan,Richard J Santen,Rakesh Kumar

doi:10.1074/jbc.m301968200

Abstract

The transcriptional activity of estrogen receptor-alpha (ER-alpha) is modified by coactivators, corepressors, and chromatin remodeling complexes. We have previously shown that the metastasis-associated protein-1 (MTA1), a component of histone deacetylase and nucleosome remodeling complexes, represses ER-driven transcription by recruiting histone deacetylases to the estrogen receptor element (ERE)-containing target gene chromatin in breast cancer cells. Using a yeast two-hybrid screening to clone MTA1-interacting proteins, we identified a previously uncharacterized molecule, which we named as MTA1-interacting coactivator (MICoA). Our findings suggest that estrogen signaling promotes nuclear translocation of MICoA and that MICoA interacts with MTA1 both in vitro and in vivo. MICoA binds to the C-terminal region of MTA1, whereas MTA1 binds to the N-terminal MICoA containing one nuclear receptor interaction LSRLL motif. We showed that MICoA is an ER coactivator, cooperates with other ER coactivators, stimulates ER-transactivation functions, and associates with the endogenous ER and its target gene promoter chromatin. MTA1 also repressed MICoA-mediated stimulation of ERE-mediated transcription in the presence of ER and ER variants with naturally occurring mutations, such as D351Y and K303R, and that it interfered with the association of MICoA with the ER-target gene chromatin. Because chromatin is a highly dynamic structure and because MTA1 and MICoA could be detected within the same complex, these findings suggest that MTA1 and MICoA might transmodulate functions of each other and any potential deregulation of MTA1 is likely to contribute to the functional inactivation of the ER pathway, presumably by derecruitment of MICoA from ER target promoter chromatin.

Highlights

The steroid hormone 17 ␤-estradiol (E2)1 plays an important role in controlling the expression of genes involved in a wide
We have previously shown that the metastasis-associated protein-1 (MTA1), a component of histone deacetylase and nucleosome remodeling complexes, represses ER-driven transcription by recruiting histone deacetylases to the estrogen receptor element (ERE)-containing target gene chromatin in breast cancer cells
Because chromatin is a highly dynamic structure and because MTA1 and MTA1-interacting coactivator (MICoA) could be detected within the same complex, these findings suggest that MTA1 and MICoA might transmodulate functions of each other and any potential deregulation of MTA1 is likely to contribute to the functional inactivation of the ER pathway, presumably by derecruitment of MICoA from ER target promoter chromatin

Summary

Introduction

The steroid hormone 17 ␤-estradiol (E2) plays an important role in controlling the expression of genes involved in a wide. The transcriptional activity of ER is affected by a number of regulatory cofactors including chromatin-remodeling complexes, coactivators, and corepressors (5–9). Coactivators generally do not bind to the DNA but are recruited to the target gene promoters through proteinprotein interactions with the ER. Evidence suggests that multiprotein complexes containing coactivators, ERs, and transcriptional regulators assemble in response to hormone binding and that they activate transcription. The molecular mechanisms of ER, the composition of the ER coactivator proteins, and the way these hormones exhibit tissue or cell type-specific responses are active areas of investigation. A structural analysis of the ER coactivators has identified a 5-amino acid NR motif LXXLL (where X is any amino acid) that can mediate coregulator binding to the liganded ERs (17–19).

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Conclusion