The human homologue of the yeast DNA repair and TFIIH regulator MMS19 is an AF-1-specific coactivator of estrogen receptor.
Steroid/nuclear hormone receptors are ligand-dependent transcriptional regulators that control gene expression in a wide array of biological processes. The transcriptional activity of the receptors is mediated by an N-terminal ligand-independent transcriptional activation function AF-1 and a C-terminal ligand-dependent transcriptional activation function AF-2. The nuclear receptor coactivator RAC3 (also known as ... AIB1/ACTR/pCIP/TRAM-1/SRC-3) is amplified in breast cancer cells, where it forms a complex with estrogen receptor (ER) and enhances AF-2 activity of the receptor. Here, we identify a putative human homologue of the yeast DNA repair and transcriptional regulator MMS19 as a RAC3-interacting protein. The human MMS19 interacts with the N-terminal PAS-A/B domain of RAC3 in vivo and in vitro through a conserved C-terminal domain. Interestingly, the human MMS19 also interacts with estrogen receptors in a ligand-independent manner but not with retinoic acid receptor or thyroid hormone receptor. Overexpression of the interacting domain of hMMS19 strongly inhibits ER-mediated transcriptional activation, indicating a dominant negative activity. In contrast, over expression of the full-length hMMS19 enhances ER-mediated transcriptional activation. We find that hMMS19 stimulates the AF-1 activity of ERalpha, but not the AF-2 activity, suggesting that hMMS19 may be an AF-1-specific transcriptional coactivator of estrogen receptor.
Mesh Terms:
Amino Acid Sequence, Cell Line, Cloning, Molecular, DNA Repair, Fungal Proteins, Humans, Molecular Sequence Data, Nuclear Receptor Coactivator 3, Proteins, Receptors, Estrogen, Receptors, Interferon, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, TATA-Binding Protein Associated Factors, Trans-Activators, Transcription Factor TFIID, Transcription Factor TFIIH, Transcription Factors, Transcription Factors, TFII, Transcriptional Activation, Tumor Cells, Cultured, Two-Hybrid System Techniques, Yeasts
Amino Acid Sequence, Cell Line, Cloning, Molecular, DNA Repair, Fungal Proteins, Humans, Molecular Sequence Data, Nuclear Receptor Coactivator 3, Proteins, Receptors, Estrogen, Receptors, Interferon, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, TATA-Binding Protein Associated Factors, Trans-Activators, Transcription Factor TFIID, Transcription Factor TFIIH, Transcription Factors, Transcription Factors, TFII, Transcriptional Activation, Tumor Cells, Cultured, Two-Hybrid System Techniques, Yeasts
J. Biol. Chem.
Date: Jun. 29, 2001
PubMed ID: 11279242
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