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Interaction between retinoic acid and vitamin D signaling pathways
M Schräder1, I Bendik, M Becker-André
1Clinique de Dermatologie, Hôpital Cantonal Universitaire, Genève, Switzerland.
The Journal of Biological Chemistry
|August 25, 1993
Summary
Nuclear receptors for vitamin D and retinoids interact, revealing new gene regulation pathways. Vitamin D and retinoic acid signaling converge through VDR-RAR heterodimers, enhancing gene expression.
Area of Science:
- Molecular Endocrinology
- Nuclear Receptor Signaling
Background:
- Nuclear signaling pathways for retinoids and vitamin D involve distinct receptors with varying response element specificities.
- Both retinoic acid receptors (RARs) and vitamin D receptors (VDRs) can act through retinoid X receptor (RXR)-dependent and -independent pathways.
- RXRs function as homodimers, and specific response elements dictate receptor binding and activation.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the interaction between vitamin D and retinoic acid signaling pathways.
- To elucidate the role of specific response elements and receptor heterodimers in mediating gene expression.
- To explore how vitamin D and all-trans-retinoic acid (ATRA) influence gene regulation via VDR-RAR heterodimers.
Main Methods:
- Conversion of a retinoid-specific response element from the RARβ promoter to a vitamin D/retinoic acid response element from the osteocalcin promoter.
- Analysis of VDR and RXR homodimer binding to specific DNA motifs (RGGTGA).
- Investigation of heterodimer formation (VDR-RAR) and their binding to response elements, assessing activation by different retinoids and vitamin D.
Main Results:
- VDR homodimers bind to the RGGTGA motif, while RXR homodimers bind to an extended osteocalcin element containing an imperfect direct repeat.
- A VDR-RAR heterodimer binds to the osteocalcin response element, mediating activation by ATRA, but not by vitamin D alone.
- Vitamin D enhances VDR-RAR heterodimer-mediated gene expression in the presence of ATRA, suggesting a synergistic interaction.
Conclusions:
- Nuclear signaling by retinoic acid and vitamin D can directly interact, expanding combinatorial gene regulation possibilities.
- VDR-RAR heterodimers play a crucial role in mediating cross-talk between vitamin D and retinoid signaling pathways.
- This interaction provides a more complex regulatory network for gene expression controlled by these essential nuclear receptors.