The goal of this project is to understand the mechanism by which the progesterone receptor (PR) interacts with and remodels chromatin at target genes in vivo using the mouse mammary tumor virus (MMTV) promoter as a model system. In the non-activated state, this promoter has a chromatin structure repressive to transcription when it exists in a stably-replicating form, either integrated into the cellular genome or as an episome. Upon binding by the liganded glucocorticoid receptor (GR), the promoter undergoes a chromatin remodeling event which is mechanistically involved in the activation of transcription. Our previous work has shown that the GR and PR have different requirements for chromatin remodeling at the MMTV promoter even though they bind to the same DNA sequences in the promoter. Our observations may form the basis for a mechanism by which the GR and PR control expression of distinct sets of target genes in vivo. Our current work shows that the PR can exist in two distinct states in cultured mammary adenocarcinoma cells. In one state, it can neither remodel chromatin nor activate transcription at the MMTV promoter, and its action may be restricted to target genes which do not require remodeling. In addition, this form of the PR can be activated by other signal transduction pathways in a progestin-independent fashion. In the second state, the PR is able to remodel and activate the MMTV promoter in chromatin, but is refractory to ligand-independent activation. We have also shown that the PR can be converted from the first state to the second by some form of cellular processing. This may represent a mechanism by which cells can restrict or expand the activity of the PR in vivo. To better define the processing mechanism we are currently examining what cellular proteins the PR interacts with in the two states. In addition, we are studying the localization and trafficking of the PR in the two states.
- National Institutes of Health: $29,728.00
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