Back to Search
Start Over
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.
- Source :
-
Molecular endocrinology (Baltimore, Md.) [Mol Endocrinol] 2006 Sep; Vol. 20 (9), pp. 2122-40. Date of Electronic Publication: 2006 Apr 27. - Publication Year :
- 2006
-
Abstract
- 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 alpha-6 integrin and 11beta-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.
- Subjects :
- Animals
Cell Line
Chlorocebus aethiops
Hormones metabolism
Humans
Ligands
Nuclear Receptor Coactivator 1
Origin Recognition Complex genetics
Protein Binding
Protein Subunits genetics
Protein Subunits metabolism
Receptors, Progesterone genetics
Receptors, Steroid metabolism
Signal Transduction
Transcription Factors
Histone Acetyltransferases metabolism
Origin Recognition Complex metabolism
Receptors, Progesterone metabolism
Transcription, Genetic genetics
Transcriptional Activation genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0888-8809
- Volume :
- 20
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Molecular endocrinology (Baltimore, Md.)
- Publication Type :
- Academic Journal
- Accession number :
- 16645042
- Full Text :
- https://doi.org/10.1210/me.2005-0149