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Selective alteration of gene expression in response to natural and synthetic retinoids
Céline Brand1, Pascaline Ségard, Pascal Plouvier
1INSERM U 459 and Ligue nationale contre le Cancer, Faculté de Médecine Henri Warembourg, 1, place de Verdun, 59045 Lille cedex, France. brand@lille.inserm.fr
Background:
Retinoids are very potent inducers of cellular differentiation and apoptosis, and are efficient anti-tumoral agents. Synthetic retinoids are designed to restrict their toxicity and side effects, mostly by increasing their selectivity toward each isotype of retinoic acids receptors (RARalpha,beta, gamma and RXRalpha, beta, gamma). We however previously showed that retinoids displayed very different abilities to activate retinoid-inducible reporter genes, and that these differential properties were correlated to the ability of a given ligand to promote SRC-1 recruitment by DNA-bound RXR:RAR heterodimers. This suggested that gene-selective modulation could be achieved by structurally distinct retinoids.
Results:
Using the differential display mRNA technique, we identified several genes on the basis of their differential induction by natural or synthetic retinoids in human cervix adenocarcinoma cells. Furthermore, this differential ability to regulate promoter activities was also observed in murine P19 cells for the RARbeta2 and CRABPII gene, showing conclusively that retinoid structure has a dramatic impact on the regulation of endogenous genes.
Conclusions:
Our findings therefore show that some degree of selective induction or repression of gene expression may be achieved when using appropriately designed ligands for retinoic acid receptors, extending the concept of selective modulators from estrogen and peroxisome proliferator activated receptors to the class of retinoid receptors.
Insights
Structurally distinct retinoids can selectively modulate gene expression by targeting retinoic acid receptors (RARs) and retinoid X receptors (RXRs). This offers a pathway for developing targeted anti-cancer therapies with reduced side effects.
Area of Science:
- Molecular Biology
- Cell Biology
- Pharmacology
Background:
- Retinoids are potent inducers of cellular differentiation and apoptosis with anti-tumoral properties.
- Synthetic retinoids aim to reduce toxicity by increasing selectivity for retinoic acid receptors (RARs) and retinoid X receptors (RXRs).
- Previous studies indicated that retinoid structure influences the activation of retinoid-inducible reporter genes, linked to SRC-1 recruitment by RXR:RAR heterodimers.
Purpose of the Study:
- To investigate whether structurally distinct retinoids can achieve gene-selective modulation of gene expression.
- To explore the impact of retinoid structure on the regulation of endogenous genes.
- To extend the concept of selective modulators to retinoid receptors.
Main Methods:
- Differential display mRNA technique to identify differentially induced genes.
- Analysis of retinoid effects on promoter activities in human cervix adenocarcinoma cells and murine P19 cells.
- Assessment of gene regulation by natural and synthetic retinoids.
Main Results:
- Several genes were identified based on differential induction by various retinoids in human cervix adenocarcinoma cells.
- Differential regulation of promoter activities, including RARbeta2 and CRABPII, was observed in murine P19 cells.
- Retinoid structure was shown to have a significant impact on the regulation of endogenous genes.
Conclusions:
- Appropriately designed retinoid ligands can achieve selective induction or repression of gene expression.
- This selective modulation extends the concept of selective modulators from other nuclear receptors to retinoid receptors.
- Findings support the development of targeted retinoid-based therapies.
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