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Transcriptional control by steroid hormones
M Truss1, G Chalepakis, B Piña
1Institut für Molekularbiologie und Tumorforschung, Marburg, Fed. Rep. Germany.
Abstract:
Gene regulation by steroid hormones leads to induction or repression of particular sets of genes. These effects are mediated by intracellular hormone receptors that, in the unliganded state, are maintained in an inactive form by unknown mechanisms possibly involving association with other cellular proteins. Induction of the mouse mammary tumor virus (MMTV) requires binding of the hormone receptor to a complex hormone-responsive element (HRE) located between 75 and 190 bp upstream from the start of transcription. The interaction of several receptor molecules with the four receptor binding sites in the HRE is highly cooperative on circular DNA molecules and each individual site is needed for optimal induction. In chromatin the HRE is precisely organized in phased nucleosomes. Following hormone treatment and receptor binding, changes in chromatin structure are detected that correlate with binding of transcription factors, including nuclear factor I, to the MMTV promoter. However, though nuclear factor I acts as a basal transcription factor on the MMTV promoter it does not cooperate with the hormone receptors in terms of binding to free DNA, and mutation of the nuclear factor I binding site does not eliminate hormonal stimulation. This residual induction is mediated by octamer motifs, upstream of the TATA box, that bind the ubiquitous transcription factor OTF-1. Mutation of these octamer motifs does not influence basal transcription in vitro, but completely abolishes the stimulatory effect of progesterone receptor.
Insights
Steroid hormones regulate genes via intracellular receptors. For mouse mammary tumor virus (MMTV) induction, hormone receptors bind to a hormone-responsive element (HRE), with OTF-1 mediating residual progesterone receptor stimulation.
Area of Science:
- Molecular Biology
- Gene Regulation
- Endocrinology
Background:
- Steroid hormones regulate gene expression through intracellular receptors.
- Unliganded receptors are kept inactive by unknown mechanisms, possibly involving protein interactions.
- Gene induction by hormones requires receptor binding to specific DNA sequences called hormone-responsive elements (HREs).
Purpose of the Study:
- To investigate the mechanisms of gene regulation by steroid hormones, focusing on the mouse mammary tumor virus (MMTV) promoter.
- To understand the role of transcription factors and chromatin structure in hormone-induced gene expression.
Main Methods:
- Analysis of hormone receptor binding to the MMTV hormone-responsive element (HRE).
- Investigation of chromatin structure changes upon hormone treatment.
- Assessing the role of transcription factors Nuclear Factor I and OTF-1 in MMTV gene induction.
Main Results:
- Hormone receptor binding to the MMTV HRE is cooperative and requires multiple binding sites.
- Hormone treatment induces chromatin structure changes and recruits transcription factors like Nuclear Factor I.
- While Nuclear Factor I is a basal transcription factor, OTF-1 binding to octamer motifs is crucial for progesterone receptor-mediated MMTV induction.
Conclusions:
- Steroid hormone-induced gene regulation involves complex interactions between hormone receptors, HREs, and transcription factors.
- Chromatin remodeling plays a significant role in mediating hormonal effects on gene expression.
- OTF-1 is essential for the stimulatory effect of progesterone receptor on MMTV transcription, highlighting its role beyond basal transcription.