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

Abstract

The transcriptional activity of estrogen receptor-␣ (ER-␣) 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.

Prediction of high risk Ewing's sarcoma by gene expression profiling

“…Therefore, MTA1 gene might be used as a therapeutic target. It was also reported that MTA1 represses ER transcription by recruiting histone deacetylases to the estrogen receptor element (ERE)-containing target gene chromatin in breast cancer cells (Mishra et al, 2003). Here we report, for the first time, the overexpression of the MTA1 gene in ES.…”

MTA1, a transcriptional activator of breast cancer amplified sequence 3

“…Previous studies have shown that MTA1 can be found in complexes containing coactivators with associated HAT (13). Therefore, we explored whether MTA1 interacts with the components of the HAT complex, and found that MTA1 associates with p300 in MCF-7 cells stably expressing T7-MTA1 (Fig.…”

“…Although MTA1 is a part of the NuRD complex and associated with HDACs, its precise function as a corepressor remained speculative until recently, when MTA1 was found to act as a repressor for ligand-induced estrogen receptor (ER) transactivation in breast cancer cells (12). Surprisingly, however, recent studies have implicated two coactivators of ER, MICoA and NRIF3, as MTA1-binding partners, giving support to the notion that coactivators and corepressors may coexist in the same complex (13,14). Furthermore, in a transgenic mouse model of MTA1 (15), up-regulation of cyclin D1 was observed, prompting the authors to speculate that MTA1 may not be a universal corepressor.…”

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

“…Transfection of si-MTA1 and the nonspecific control siRNA, si-GL3, were as described previously (Mishra et al, 2003). The pBS/U6 empty vector, si-C, and the plasmids bearing the siRNA targeting HDAC1 (pBS/U6-HDAC1) and HDAC2 (pBS/U6-HDAC2) were kindly gifted by Dr Edward Seto.…”