Steroid Receptor Induction of Gene Transcription: A Two-Step Model

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 94; no. 15; pp. 7879 - 7884
• Main Authors: Jenster, Guido, Spencer, Thomas E., Burcin, Mark M., Tsai, Sophia Y., Tsai, Ming-Jer, O'Malley, Bert W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 22.07.1997; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences of the USA
• Subjects: Acetylation; Biochemistry; Biological Sciences; Chromatin; Chromatin - genetics; Cyclic AMP Response Element-Binding Protein - physiology; Deoxyribonucleic acid; DNA; Enzyme Inhibitors - pharmacology; Genes; Histone Acetyltransferases; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids - pharmacology; Models, Biological; Molecular Sequence Data; Nuclear Proteins - metabolism; Nuclear Receptor Coactivator 1; Nucleosomes; Receptors, Progesterone - genetics; Receptors, Progesterone - metabolism; Receptors, Progesterone - physiology; Response elements; Ribonucleic acid; RNA; Steroid receptors; Steroids; Trans-Activators; Transactivation; Transcription factors; Transcription Factors - metabolism; Transcription Factors - physiology; Transcriptional Activation - physiology; Tumor Cells, Cultured
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.15.7879

Coactivators, such as steroid receptor coactivator 1 (SRC-1A) and CREB (cAMP response element binding protein)-binding protein (CBP), are required for efficient steroid receptor transactivation. Using an in vitro transcription assay, we found that progesterone receptor (PR)-driven transcription is inhibited by a dominant negative PR ligand-binding domain-interacting region of SRC-1A, indicating that SRC-1A is required for actual transcriptional processes. In addition, these coactivators also possess intrinsic histone acetyltransferase (HAT) activity and bind to each other and another HAT, p300/CBP-associated factor. Here we show that the human PR also interacts with p300/CBP-associated factor in vitro. Recruitment of multiple HATs to target promoters suggests an important role for chromatin remodeling in transcriptional activation of genes by steroid receptors. In transient transfection assays, we found that addition of a histone deacetylase inhibitor, trichostatin A, strongly potentiated PR-driven transcription. In contrast, directing histone deacetylase-1 (HD1) to a promoter using the GAL4 DNA binding domain inhibited transcription. Furthermore, PR transactivation was repressed by recruiting HD1 into the PR-DNA complex by fusing HD1 to a PR ligand-binding domain-interacting portion of SRC-1. Collectively, these results suggest that targeted histone acetylation by recruited HAT cofactors and histone deacetylation are important factors affecting PR transactivation. Recruitment of coactivators and HATs by the liganded PR in vivo may result in (i) remodeling of transcriptionally repressed chromatin to facilitate assembly and (ii) enhanced stabilization of the preinitiation complex by the activation functions of coactivators and the liganded PR itself.