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Interference of pathway specific transcription factors
H Ponta1, A C Cato, P Herrlich
1Kernforschungszentrum Karlsruhe, Institut für Genetik und Toxikologie, Germany.
Abstract:
A mechanism for reversibility of cellular decisions, e.g., proliferation or differentiation, is mediated by direct interference of pathway-specific transcription factors. Due to the relative activity of the transcription factors, genetic programs are reversibly switched on and off. In the case of the transcription factors AP-1 and the family of steroid hormone receptors (including retinoic acid receptor, thyroid hormone and vitamin D receptors) two different mechanisms account for negative interference. In one case overlapping DNA binding sites are suggestive of mutually exclusive binding of transcription factors to account for repression. In the other case, a DNA bound transcription factor is attacked by another one via protein-protein interaction, without the need of the latter factor binding to DNA. Although it is not excluded, that also in the case of overlapping DNA binding elements protein-protein interaction might in fact be responsible for repression instead of substitution, the two situations can be clearly distinguished by specific mutants in the glucocorticoid receptor and in Jun and Fos. For the interaction mechanism, we favor the interpretation that the binding of one transcription factor to another one interferes with transactivation directly without influence on DNA binding. The fact that at least two different mechanisms are established to guarantee effective interference, demonstrates how important this type of transcription factor crosstalk is.
Insights
Cellular decisions like proliferation and differentiation are reversible through transcription factor interference. Two distinct mechanisms, DNA binding competition and protein-protein interactions, regulate gene programs, highlighting crucial transcription factor crosstalk.
Area of Science:
- Molecular Biology
- Cellular Biology
- Genetics
Background:
- Cellular decisions, such as proliferation and differentiation, are regulated by genetic programs.
- Transcription factors (TFs) play a critical role in controlling these genetic programs.
- Reversibility of cellular decisions implies dynamic regulation of TF activity.
Purpose of the Study:
- To elucidate the mechanisms underlying the reversibility of cellular decisions.
- To investigate the role of direct interference between pathway-specific transcription factors.
- To understand how transcription factor crosstalk influences gene expression.
Main Methods:
- Analysis of transcription factor (TF) interactions, specifically AP-1 and steroid hormone receptors.
- Investigating two proposed mechanisms of negative interference: overlapping DNA binding sites and protein-protein interactions.
- Utilizing specific mutants of glucocorticoid receptor, Jun, and Fos to distinguish between interference mechanisms.
Main Results:
- Two distinct mechanisms of negative interference between TFs were identified: mutually exclusive DNA binding and direct protein-protein interaction.
- Protein-protein interaction mechanism interferes with transactivation without affecting DNA binding.
- Specific mutants confirmed the distinct nature of these two interference mechanisms.
Conclusions:
- Transcription factor crosstalk is essential for the reversibility of cellular decisions.
- Multiple mechanisms, including DNA binding competition and protein-protein interactions, mediate TF interference.
- Understanding these TF interactions is key to controlling cellular fate and function.