MICoA, a novel metastasis-associated protein 1 (MTA1) interacting protein coactivator, regulates estrogen receptor-alpha transactivation functions.
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.
Mishra
Sandip K
SK
Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Mazumdar
Abhijit
A
Vadlamudi
Ratna K
RK
Li
Feng
F
Wang
Rui-An
RA
Yu
Wei
W
Jordan
V Craig
VC
Santen
Richard J
RJ
Kumar
Rakesh
R
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D001943:Breast Neoplasms; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D018076:DNA, Complementary; D004622:Embryo, Mammalian; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D005260:Female; D015870:Gene Expression; D015723:Gene Library; D005982:Glutathione Transferase / Q000235:genetics; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D008321:Mammary Glands, Animal / Q000737:chemistry / Q000254:growth & development; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012333:RNA, Messenger; D011960:Receptors, Estrogen / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins; D020218:Response Elements; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques
D002843:Chromatin; D018076:DNA, Complementary; D047628:Estrogen Receptor alpha; C475169:MICoA protein, mouse; C089320:MTA1 protein, human; D010446:Peptide Fragments; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D004958:Estradiol; D005982:Glutathione Transferase; D006655:Histone Deacetylases