This proposal addresses a central question in cancer biology: What are the molecular mechanisms of steroid hormone-mediated gene regulation? Recent work has demonstrated an elaborate coupling of steroid receptor action and cellular signal transduction pathways. These studies have led to the proposal that this coupling is the result of the recruitment or activation of transcriptional coactivators mediating communication between hormone receptors and the basal transcription machinery. This research examines this hypothesis by introducing yeast or human TATA- binding protein (TBP) into hormone responsive cells. Although yeast TBP has been shown to support steroid receptor-dependent transcriptional activation in yeast, we suggest yeast TBP will not support modulation of receptor-dependent transcriptional activation by mammalian signal transduction pathways. Yeast-human TBP chimeras will then be used in an effort to map the TBP domain involved in this coupling of steroid receptor action and cell signaling pathways. This information will be exploited in protein interaction assays to isolate the coactivator mediating this coupling phenomenon. Identification of the factors involved in transcriptional regulation governed by steroid hormones will contribute greatly to our basic understanding of the interplay of cellular signaling pathways and hormone action, and will ultimately allow improved investigations into clinical responses to hormone therapy.
| Lambert, James R; Nordeen, Steven K (2003) CBP recruitment and histone acetylation in differential gene induction by glucocorticoids and progestins. Mol Endocrinol 17:1085-94 |
| Lambert, J R; Nordeen, S K (1998) Steroid-selective initiation of chromatin remodeling and transcriptional activation of the mouse mammary tumor virus promoter is controlled by the site of promoter integration. J Biol Chem 273:32708-14 |
