title: GEMIN4 functions as a coregulator of the mineralocorticoid receptor.
abstract: The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily. Pathological activation of the MR causes cardiac fibrosis and heart failure, but clinical use of MR antagonists is limited by the renal side effect of hyperkalemia. Coregulator proteins are known to be critical for nuclear receptor-mediated gene expression. Identification of coregulators, which mediate MR activity in a tissue-specific manner, may allow for the development of novel tissue-selective MR modulators that confer cardiac protection without adverse renal effects. Our earlier studies identified a consensus motif among MR-interacting peptides, MPxLxxLL. Gem (nuclear organelle)-associated protein 4 (GEMIN4) is one of the proteins that contain this motif. Transient transfection experiments in HEK293 and H9c2 cells demonstrated that GEMIN4 repressed agonist-induced MR transactivation in a cell-specific manner. Furthermore, overexpression of GEMIN4 significantly decreased, while knockdown of GEMIN4 increased, the mRNA expression of specific endogenous MR target genes. A physical interaction between GEMIN4 and MR is suggested by their nuclear co-localization upon agonist treatment. These findings indicate that GEMIN4 functions as a novel coregulator of the MR.
authors.affiliation: MIMR-PHI InstitutePO Box 5152, Clayton, Victoria 3168, AustraliaDepartment of MedicineMonash University, Clayton, Victoria 3168, AustraliaDepartment of EndocrinologyMetabolism, Rheumatology and Nephrology, Oita University, Yufu 879-5593, Japan MIMR-PHI InstitutePO Box 5152, Clayton, Victoria 3168, AustraliaDepartment of MedicineMonash University, Clayton, Victoria 3168, AustraliaDepartment of EndocrinologyMetabolism, Rheumatology and Nephrology, Oita University, Yufu 879-5593, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: MIMR-PHI InstitutePO Box 5152, Clayton, Victoria 3168, AustraliaDepartment of MedicineMonash University, Clayton, Victoria 3168, AustraliaDepartment of EndocrinologyMetabolism, Rheumatology and Nephrology, Oita University, Yufu 879-5593, Japan MIMR-PHI InstitutePO Box 5152, Clayton, Victoria 3168, AustraliaDepartment of MedicineMonash University, Clayton, Victoria 3168, AustraliaDepartment of EndocrinologyMetabolism, Rheumatology and Nephrology, Oita University, Yufu 879-5593, Japan.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Fuller
authors.affiliation: MIMR-PHI InstitutePO Box 5152, Clayton, Victoria 3168, AustraliaDepartment of MedicineMonash University, Clayton, Victoria 3168, AustraliaDepartment of EndocrinologyMetabolism, Rheumatology and Nephrology, Oita University, Yufu 879-5593, Japan.
authors.forename: James
authors.initials: J
authors.lastname: Morgan
authors.affiliation: MIMR-PHI InstitutePO Box 5152, Clayton, Victoria 3168, AustraliaDepartment of MedicineMonash University, Clayton, Victoria 3168, AustraliaDepartment of EndocrinologyMetabolism, Rheumatology and Nephrology, Oita University, Yufu 879-5593, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Shibata
authors.affiliation: MIMR-PHI InstitutePO Box 5152, Clayton, Victoria 3168, AustraliaDepartment of MedicineMonash University, Clayton, Victoria 3168, AustraliaDepartment of EndocrinologyMetabolism, Rheumatology and Nephrology, Oita University, Yufu 879-5593, Japan.
authors.forename: Colin D
authors.initials: CD
authors.lastname: Clyne
authors.affiliation: MIMR-PHI InstitutePO Box 5152, Clayton, Victoria 3168, AustraliaDepartment of MedicineMonash University, Clayton, Victoria 3168, AustraliaDepartment of EndocrinologyMetabolism, Rheumatology and Nephrology, Oita University, Yufu 879-5593, Japan MIMR-PHI InstitutePO Box 5152, Clayton, Victoria 3168, AustraliaDepartment of MedicineMonash University, Clayton, Victoria 3168, AustraliaDepartment of EndocrinologyMetabolism, Rheumatology and Nephrology, Oita University, Yufu 879-5593, Japan morag.young@princehenrys.org.
authors.forename: Morag J
authors.initials: MJ
authors.lastname: Young
mesh_terms: D000450:Aldosterone / Q000494:pharmacology; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016384:Consensus Sequence; D030562:Databases, Protein; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D017411:Ribonucleoproteins, Small Nuclear / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C406815:GEMIN4 protein, human; C000603657:Gemin4 protein, rat; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D018161:Receptors, Mineralocorticoid; D012097:Repressor Proteins; D017411:Ribonucleoproteins, Small Nuclear; D000450:Aldosterone
keywords: GEMIN4; coactivator; corepressor; mineralocorticoid receptor (MR)