title: Aberrant association of promyelocytic leukemia protein-retinoic acid receptor-alpha with coactivators contributes to its ability to regulate gene expression.
abstract: The aberrant association of promyelocytic leukemia protein-retinoic acid receptor-alpha (PML-RARalpha) with corepressor complexes is generally thought to contribute to the ability of PML-RARalpha to regulate transcription. We report here that PML-RARalpha acquires aberrant association with coactivators. We show that endogenous PML-RARalpha interacts with the histone acetyltransferases CBP, p300, and SRC-1 in a hormoneindependent manner, an association not seen for RARalpha. This hormone-independent coactivator binding activity requires an intact ligand-binding domain and the NR box of the coactivators. Confocal microscopy studies demonstrate that exogenous PML-RARalpha sequesters and colocalizes with coactivators. These observations correlate with the ability of PML-RARalpha to attenuate the transcription activation of the Notch signaling downstream effector, CBF1, and of the glucocorticoid receptor. This includes attenuation of the glucocorticoid-induced leucine zipper (GILZ) and FLJ25390 target genes of the endogenous glucocorticoid receptor. Furthermore, treatment of NB4 cells with all-trans-retinoic acid, which promotes PML-RARalpha degradation, resulted in increased activation of GILZ. On the basis of these findings, we propose a model in which the hormone-independent association between PML-RARalpha and coactivators contributes to its ability to regulate gene expression.
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio 44106.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Reineke
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio 44106.
authors.forename: Heng
authors.initials: H
authors.lastname: Liu
authors.affiliation: Research Institute of University Hospitals of Cleveland and the Comprehensive Cancer Center of Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106.
authors.forename: Minh
authors.initials: M
authors.lastname: Lam
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio 44106.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio 44106. Electronic address: hxk43@cwru.edu.
authors.forename: Hung-Ying
authors.initials: HY
authors.lastname: Kao
mesh_terms: D000818:Animals; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; D051880:Receptors, Notch; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D005982:Glutathione Transferase