Abstract
Expression of keratin proteins, markers of epidermal differentiation and pathology, is uniquely regulated by the nuclear receptors for retinoic acid (RAR) and thyroid hormone (T3R) and their ligands: it is constitutively activated by unliganded T3R, but it is suppressed by ligand-occupied T3R or RAR. This regulation was studied using gel mobility shift assays with purified receptors and transient transfection assays with vectors expressing various receptor mutants. Regulation of keratin gene expression by RAR and T3R occurs through direct binding of these receptors to receptor response elements of the keratin gene promoters. The DNA binding "C" domain of these receptors is essential for both ligand-dependent and -independent regulation. However, the NH2-terminal "A/B" domain of T3R is not required for either mode of regulation of keratin gene expression. Furthermore, v-ErbA, an oncogenic derivative of cT3R, also activates keratin gene expression. In contrast to the previously described mechanism of gene regulation by T3R, heterodimerization with the retinoid X receptor is not essential for activation of keratin gene expression by unliganded T3R. These findings indicate that the mechanism of regulation of keratin genes by RAR and T3R differs significantly from the mechanisms described for other genes modulated by these receptors.
Highlights
Hormones and vitamins, such as thyroid hormone (T3)1 and all-trans-retinoic acid (RA), are important regulators of development and differentiation in general and of the epidermis in particular
When the basal keratinocyte becomes detached from the basement membrane, its commitment to differentiation is announced by suppression of the basal cell-specific keratins K5/ K14 and the induction of the differentiation-specific keratins K1/K10 [13, 14]
Novel Regulation of the Keratin Promoters by Retinoic Acid and Thyroid Hormone Receptors—To analyze regulation of keratin gene expression by RA and T3 we used the promoters of the K14, K5, and K17 keratin genes linked to a CAT reporter gene
Summary
Hormones and vitamins, such as thyroid hormone (T3) and all-trans-retinoic acid (RA), are important regulators of development and differentiation in general and of the epidermis in particular. The effects of vitamin A, a precursor of RA, on the skin were observed first in 1922 [1]. ¶ Recipient of a Ken Burdick Memorial Fellowship Award granted through the Dermatology Foundation. Thyroid hormone deficiency results in a number of skin changes, including hyperkeratosis [7,8,9,10], and the thyroid hormone excess causes increased epidermal cell division [11]. Keratins are the intermediate filament network proteins in many epithelia. Their expression is precisely controlled in various physiological and pathological states of the epidermis. Keratin K17 is expressed, whereas transformed keratinocytes express keratins K8/K18 [17, 18]
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