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Regulation of keratin gene expression: the role of the nuclear receptors for retinoic acid, thyroid hormone, and vitamin D3.

Keratinization, the orderly process of differentiation of epidermal keratinocytes from stratum basale to stratum corneum, is influenced by hormones and vitamins. We have used expression of epidermal keratins as a paradigm of keratinization processes and analyzed the effects of retinoic acid, thyroid hormone, and vitamin D3 on keratin gene expression. DNA constructs in which keratin gene promoters drive expression of reporter genes were co-transfected with vectors expressing nuclear receptors for the above molecules into various cell types. The keratin promoters studied included K3, K5, K10, K14, and K16. The recipient cell types were HeLa and primary cultures of rabbit corneal and esophageal epithelial cells and of human epidermal keratinocytes. We found that retinoic acid, via its nuclear receptor, suppresses expression of all the above-listed keratin genes. Thyroid hormone and its receptor similarly suppressed those genes. The site of interaction between these two receptors and the promoter sequences of K10 and K14 genes has been identified. Surprisingly, vitamin D3 and its receptor had no direct effect on keratin promoters. Our results suggest that a retinoic acid has a twofold effect on keratin gene expression: by regulating keratinocyte differentiation it determines which keratins are expressed, basal cell specific or differentiation specific; by direct interaction between its receptor and keratin genes, retinoic acid determines the total amount of keratin protein within the cell. Vitamin D3, on the other hand, also regulates keratinocyte differentiation, but does not directly interact with the keratin genes.