title: Metastasis-associated protein 1 interacts with NRIF3, an estrogen-inducible nuclear receptor coregulator.
abstract: The transcriptional activity of estrogen receptor alpha (ER-alpha) is modified by regulatory action and interactions of coactivators and corepressors. Recent studies have shown that the metastasis-associated protein 1 (MTA1) represses estrogen receptor element (ERE)-driven transcription in breast cancer cells. With a yeast two-hybrid screen to clone MTA1-interacting proteins, we identified a known nuclear receptor coregulator (NRIF3) as an MTA1-binding protein. NRIF3 interacted with MTA1 both in vitro and in vivo. NRIF3 bound to the C-terminal region of MTA1, while MTA1 bound to the N-terminal region of NRIF3, containing one nuclear receptor interaction LXXLL motif. We showed that NRIF3 is an ER coactivator, hyperstimulated ER transactivation functions, and associated with the endogenous ER and its target gene promoter. MTA1 repressed NRIF3-mediated stimulation of ERE-driven transcription and interfered with NRIF3's association with the ER target gene chromatin. In addition, NRIF3 deregulation enhanced the responsiveness of breast cancer cells to estrogen-induced stimulation of growth and anchorage independence. Furthermore, we found that NRIF3 is an estrogen-inducible gene and activated ER associated with the ER response element in the NRIF3 gene promoter. These findings suggest that NRIF3, an MTA1-interacting protein, is an estrogen-inducible gene and that regulatory interactions between MTA1 and NRIF3 might be important in modulating the sensitivity of breast cancer cells to estrogen.
authors.affiliation: Departments of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Amjad H
authors.initials: AH
authors.lastname: Talukder
authors.forename: Anupama
authors.initials: A
authors.lastname: Gururaj
authors.forename: Sandip K
authors.initials: SK
authors.lastname: Mishra
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D020816:Amino Acid Motifs; D015152:Blotting, Northern; D015153:Blotting, Western; D002455:Cell Division; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000494:pharmacology; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015534:Trans-Activators; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques
chemical_list: D002843:Chromatin; D018076:DNA, Complementary; D047628:Estrogen Receptor alpha; D004967:Estrogens; C403295:ITGB3BP protein, human; C089320:MTA1 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D015534:Trans-Activators; D005982:Glutathione Transferase; D006655:Histone Deacetylases