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Progesterone receptor deficient in chromatin binding has an altered cellular state
Jeannine Botos1, Wenjuan Xian, David F Smith
1Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, Maryland 20892-5055, USA. smithcat@exchange.nih.gov
The Journal of Biological Chemistry
|January 28, 2004
Summary
Progesterone receptor (PR) exists in distinct functional states in cancer cells, differing in cellular location and chaperone interactions. Subcellular distribution significantly impacts PR function and transcriptional activity.
Area of Science:
- Molecular biology
- Cell biology
- Biochemistry
Background:
- Progesterone receptor (PR) exhibits distinct functional states in mammary adenocarcinoma cells.
- Functional differences include promoter activation, ligand sensitivity, and ligand-independent activation.
Purpose of the Study:
- To investigate if altered cellular processing underlies the distinct functional states of PR.
- To biochemically characterize the composition and distribution of functionally distinct PRs.
Main Methods:
- Biochemical partitioning to separate cytosolic and nuclear PR fractions.
- Coimmunoprecipitation to analyze PR-chaperone interactions.
- Assessment of transcriptional activity and promoter association.
Main Results:
- Unliganded PR partitions differently between cytosolic and nuclear fractions.
- Cytosolic PR associates with hsp90 and p23; nuclear PR associates with hsp90, p23, FKBP51, and is dimerized/phosphorylated.
- Hormone treatment reduces PR-chaperone complexes; hsp90 inhibitor blocks transcriptional activity.
- Distinct PR forms show differential association with chromatin-bound promoters.
Conclusions:
- Subcellular distribution and composition of PR complexes significantly impact function in mammary adenocarcinoma cells.
- Differences in PR processing and localization influence its transcriptional activity.
- Transiently expressed steroid receptors may not perfectly mimic endogenous receptor processing.