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Retinoic acid is a negative regulator of AP-1-responsive genes
R Schüle1, P Rangarajan, N Yang
1Howard Hughes Medical Institute, La Jolla, CA.
Abstract:
We present evidence that retinoic acid can down-regulate transcriptional activation by the nuclear protooncogene c-jun. All three members of the retinoic acid receptor (RAR) subfamily (RAR alpha, RAR beta, and RAR gamma) can repress transcriptional induction of the human collagenase gene or a heterologous promoter that contains the collagenase promoter AP-1-binding site. In contrast, the retinoid X receptor fails to repress Jun/AP-1 activity, demonstrating a significant difference between the two regulatory systems through which retinoids exert their transcriptional control. Analysis of RAR alpha mutants in transfection studies reveals that the DNA-binding domain is important for the inhibition of Jun/AP-1 activity, even though the RAR does not bind the collagenase AP-1 site. Rather, gel-retardation assays reveal that bacterially expressed full-length RAR alpha inhibits binding of Jun protein to target DNA. These data suggest that the RAR alpha may form a nonproductive complex with c-Jun and provides a simple mechanisms by which retinoic acid may limit cell growth and possibly malignant progression.
Insights
Retinoic acid (RA) can suppress gene activation by the c-Jun protooncogene. Retinoic acid receptors (RARs) inhibit Jun/AP-1 activity, suggesting a mechanism for RA in limiting cell growth and potential malignant progression.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- The nuclear protooncogene c-Jun plays a critical role in transcriptional activation.
- Retinoic acid and its receptors (RARs) are known regulators of gene expression.
- Understanding the interplay between c-Jun and retinoid signaling is crucial for cell growth and cancer research.
Purpose of the Study:
- To investigate the effect of retinoic acid on transcriptional activation mediated by c-Jun.
- To determine the role of different retinoic acid receptor subfamilies in this process.
- To elucidate the mechanism by which retinoic acid influences c-Jun activity.
Main Methods:
- Transfection studies using RAR alpha mutants.
- Analysis of transcriptional induction of the human collagenase gene and a heterologous promoter.
- Gel-retardation assays with bacterially expressed RAR alpha.
Main Results:
- All three RAR subfamily members (RAR alpha, beta, gamma) repressed transcriptional induction involving the c-Jun/AP-1 site.
- The retinoid X receptor did not repress Jun/AP-1 activity, highlighting distinct retinoid regulatory systems.
- RAR alpha's DNA-binding domain was essential for inhibiting Jun/AP-1 activity, despite RAR alpha not binding the AP-1 site directly.
- RAR alpha inhibited the binding of c-Jun protein to DNA.
Conclusions:
- Retinoic acid receptors (RARs) can down-regulate c-Jun-mediated transcriptional activation.
- RAR alpha may form a nonproductive complex with c-Jun, inhibiting its DNA binding.
- This interaction provides a potential mechanism for retinoic acid in limiting cell proliferation and malignant progression.