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Ligand-Controlled Interaction of Histone Acetyltransferase Binding to ORC-1 (HBO1) with the N-Terminal Transactivating Domain of Progesterone Receptor Induces Steroid Receptor Coactivator 1-Dependent Coactivation of Transcription

Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 693 (A.G.-M., B.D., G.M., H.L., L.R., M.G., M.L., S.W.), Récepteurs Stéroïdiens, Physiopathologie Endocrinienne et Métabolique, Faculté de Médecine Paris-Sud, 94276 Le Kremlin-Bicêtre Cedex, France; Centre National de la Recherche Scientifique (CNRS), Unité Propre de Recherche 9079 (A.C.), Institut Andre Lwoff, 94800 Villejuif, France; Biochimie Hormonale (E.M.), Hôpital de Bicêtre, 94275 Le Kremlin-Bicêtre, France; Department of Molecular and Cellular Biology (L.A.), Baylor College of Medicine, Houston, Texas 77030; Unité de Médecine Vasculaire (N.C.-B.), Hôpital Tenon Assistance Publique-Hôpitaux de Paris, 75020 Paris, France; and Department of Reproduction and Development and Obstetrics and Gynaecology (L.J.B., C.W.B.), Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Hugues Loosfelt, Institut National de la Santé et de la Recherche Médicale, Unité 693, Faculté de Médecine Paris-Sud, 63 rue Gabriel Péri, 94276 Le Kremlin-Bicêtre Cedex, France. E-mail: hugues.loosfelt{at}kb.u-psud.fr.

Modulators of cofactor recruitment by nuclear receptors are expected to play an important role in the coordination of hormone-induced transactivation processes. To identify such factors interacting with the N-terminal domain (NTD) of the progesterone receptor (PR), we used this domain as bait in the yeast Sos-Ras two-hybrid system. cDNAs encoding the C-terminal MYST (MOZ-Ybf2/Sas3-Sas2-Tip60 acetyltransferases) domain of HBO1 [histone acetyltransferase binding to the origin recognition complex (ORC) 1 subunit], a member of the MYST acetylase family, were thus selected from a human testis cDNA library. In transiently transfected CV1 cells, the wild-type HBO1 [611 amino acids (aa)] enhanced transcription mediated by steroid receptors, notably PR, mineralocorticoid receptor, and glucocorticoid receptor, and strongly induced PR and estrogen receptor coactivation by steroid receptor coactivator 1a (SRC-1a). As assessed by two-hybrid and glutathione-S-transferase pull-down assays, the HBO1 MYST acetylase domain (aa 340–611) interacts mainly with the NTD, and also contacts the DNA-binding domain and the hinge domains of hormone-bound PR. The HBO1 N-terminal region (aa 1–340) associates additionally with PR ligand-binding domain (LBD). HBO1 was found also to interact through its NTD with SRC-1a in the absence of steroid receptor. The latter coassociation enhanced specifically activation function 2 activation function encompassed in the LBD. Conversely, the MYST acetylase domain specifically enhanced SRC-1 coupling with PR NTD, through a hormone-dependent mechanism. In human embryonic kidney 293 cells expressing human PRA or PRB, HBO1 raised selectively an SRC-1-dependent response of PRB but failed to regulate PRA activity. We show that HBO1 acts through modification of an LBD-controlled structure present in the N terminus of PRB leading to the modulation of SRC-1 functional coupling with activation function 3-mediated transcription. Importantly, real-time RT-PCR analysis also revealed that HBO1 enhanced SRC-1 coactivation of PR-dependent transcription of human endogenous genes such as -6 integrin and 11ß-hydroxydehydrogenase 2 but not that of amphiregulin. Immunofluorescence and confocal microscopy of human embryonic kidney-PRB cells demonstrated that the hormone induces the colocalization of HBO1 with PR-SRC-1 complex into nuclear speckles characteristic of PR-mediated chromatin remodeling. Our results suggest that HBO1 might play an important physiological role in human PR signaling.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  GR  |  MR  |  PR

Coregulators:   Tip60  |  HBO1  |  SRC-1

Ligands:   Dexamethasone  |  17β-Estradiol  |  Dihydrotestosterone  |  Aldosterone  |  R5020

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