Dominant-negative Retinoic Acid Receptors Elicit Epidermal Defects through a Non-canonical Pathway

Previous work has shown that a dominant-negative retinoic acid receptor α (dnRARα), expressed under the K14 promoter, causes severe epidermal defects. Similar defects are, however, not seen in RARαγ double null mutant mice, which lack the entire complement of RARs expressed in the epidermis. To inve...

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Bibliographic Details
Published in:The Journal of biological chemistry 2005-01, Vol.280 (4), p.3012-3021
Main Authors: Chen, Chang Feng, Lohnes, David
Format: Article
Language:English
Subjects:
Animals
COS Cells
DNA - metabolism
DNA, Complementary - metabolism
Dose-Response Relationship, Drug
Down-Regulation
Epidermis - metabolism
Epidermis - pathology
Genes, Dominant
Immunohistochemistry
Keratinocytes - metabolism
Keratins - metabolism
Mice
Mice, Transgenic
Models, Genetic
Mutagenesis, Site-Directed
Mutation
Phenotype
Phosphoproteins - genetics
Promoter Regions, Genetic
Protein Binding
Receptors, Retinoic Acid - genetics
Receptors, Retinoic Acid - physiology
Retinoic Acid Receptor alpha
Signal Transduction
Time Factors
Trans-Activators - genetics
Transfection
Transgenes
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Summary:Previous work has shown that a dominant-negative retinoic acid receptor α (dnRARα), expressed under the K14 promoter, causes severe epidermal defects. Similar defects are, however, not seen in RARαγ double null mutant mice, which lack the entire complement of RARs expressed in the epidermis. To investigate the mechanism of action of these dominant-negative receptors, dnRARα or a DNA binding-deficient variant, dnRARαDBD, were targeted to the basal epidermis. Expression of either receptor type led to similar epidermal phenotypes suggesting that both RAR mutants acted through a common mechanism. The epidermal phenotype was reminiscent of defects seen in p63-/- mice. Consistent with this, reduced p63 expression was observed in transgenic offspring expressing either RAR mutant, suggesting that down-regulation of p63 might underlie the effects of these receptors on epidermal development. By contrast, expression of p63 in the epidermis of RARαγ-/- offspring was unaffected, indicating that RARs were not essential for p63 expression. These findings suggest that dnRARs may impact on epidermal development through one or more non-canonical pathways, which are independent of receptor-DNA interaction.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M411522200