Title

The human homologue of the yeast DNA repair and TFIIH regulator MMS19 is an AF-1-specific coactivator of estrogen receptor

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Date

3-30-2001

Document Type

Article

Subjects

Amino Acid Sequence; Cell Line; Cloning, Molecular; DNA Repair; Fungal Proteins; Humans; Molecular Sequence Data; *Proteins; Receptors, Estrogen; Receptors, Interferon; *Saccharomyces cerevisiae Proteins; Sequence Homology, Amino Acid; *TATA-Binding Protein Associated Factors; Trans-Activation (Genetics); Trans-Activators; *Transcription Factor TFIID; Transcription Factor TFIIH; Transcription Factors; *Transcription Factors, TFII; Tumor Cells, Cultured; Two-Hybrid System Techniques; Yeasts

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Citation: J Biol Chem. 2001 Jun 29;276(26):23962-8. Epub 2001 Mar 28. Link to article on publisher's site

DOI of Published Version

10.1074/jbc.M101041200

Related Resources

Link to Article in PubMed

Journal Title

The Journal of biological chemistry

PubMed ID

11279242