RESUMEN
BACKGROUND: ERBIN is a binding partner of Erb-B2, an orphan receptor within the Erb-B family critically involved in the regulation of cell growth and differentiation. Although its function remains unclear, ERBIN is thought to affect the polarity of epithelial cells and cell growth via the Ras signalling pathway. OBJECTIVES: To examine and compare the tissue distribution and the expression levels of ERBIN and Erb-B2 in normal skin and in cutaneous carcinomas. METHODS: Fifteen cases of basal cell carcinoma (BCC), 12 cases of squamous cell carcinoma (SCC) and five cases of keratoacanthoma (KA) were analysed by immunohistochemistry on paraffin-embedded sections using anti-ERBIN and anti-Erb-B2 antibodies. RESULTS: ERBIN and Erb-B2 had a similar distribution in normal human skin. They were primarily localized at the plasma membrane in differentiated keratinocytes and in duct cells from eccrine glands, whereas they were localized diffusely in the cytoplasma of basal keratinocytes. In both SCC and KA the subcellular distribution of ERBIN and Erb-B2 remained unchanged, whereas both proteins were redistributed from the plasma membrane into cytosolic aggregates in BCC. CONCLUSIONS: The subcellular localization of ERBIN in normal human skin is similar to that of Erb-B2 and varies with cell differentiation. Based on our findings and on the biological activities of Erb-B2, it is conceivable that disturbed expression or functioning of ERBIN and Erb-B2 is implicated in the development of the malignant phenotype of BCC.
Asunto(s)
Carcinoma Basocelular/química , Carcinoma de Células Escamosas/química , Proteínas Portadoras/análisis , Queratinocitos/química , Receptor ErbB-2/análisis , Neoplasias Cutáneas/química , Proteínas Adaptadoras Transductoras de Señales , Western Blotting/métodos , Estudios de Casos y Controles , Línea Celular , Membrana Celular/química , Citosol/química , Técnica del Anticuerpo Fluorescente , Humanos , Piel/químicaRESUMEN
CD44 is a polymorphic integral membrane glycoprotein that serves as the principal cell surface receptor for hyaluronate, the major component of the extracellular matrix. CD44 is abundantly found in the skin and functions as a cell adhesion molecule. In a recent study we have observed a massive dermal accumulation of hyaluronate as a result of the in vivo selective suppression of CD44 in keratinocytes in mice expressing a keratin 5 promoter-driven CD44 anti-sense transgene. As the histologic features of the dorsal skin of these transgenic mice display some similarities to those of the skin lesions of lichen sclerosus et atrophicus, we explored the nature of the material accumulated in the dermis of genital and extragenital lesions of 14 patients with lichen sclerosus et atrophicus by Alcian Blue and human CD44 receptor globulin stainings, as well as the epidermal expression of CD44 protein and mRNA by immunohistochemistry and in situ hybridization. In this study we provide evidence that hyaluronate is accumulated in the superficial dermis of lichen sclerosus et atrophicus lesions, in particular by the use of human CD44 receptor globulin staining, which binds specifically to hyaluronate. In addition we show that the protein and mRNA expression of CD44 in the epidermis of the involved lichen sclerosus et atrophicus skin from genital and extragenital areas is significantly decreased, and in some cases completely lost. In contrast, keratinocyte CD44 expression was un-altered in the skin lesions of lupus erythematosus, scleroderma and reticular erythematous mucinosis, despite the presence of a mucinous material in the dermis. These results suggest that a decrease in CD44 in the keratinocytes may be correlated with an abnormal dermal accumulation of hyaluronate in the lesions of lichen sclerosus et atrophicus, and may play a pathogenetic role in this disease. J Invest Dermatol 115:1054-1058 2000
Asunto(s)
Receptores de Hialuranos/biosíntesis , Ácido Hialurónico/biosíntesis , Liquen Escleroso y Atrófico/metabolismo , Piel/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Femenino , Genitales Femeninos , Genitales Masculinos , Humanos , Hialina/metabolismo , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana EdadRESUMEN
Expression of epidermal-type fatty acid-binding protein (E-FABP) and S100A7 has previously been shown to be elevated in psoriatic skin, a disease characterized by abnormal keratinocyte differentiation. However, no causal relationship between the up-regulation of these proteins and the disease has been shown. E-FABP is thought to be involved in cytosolic fatty acid (FA) transport, whereas the role of S100A7 is still unknown. In this report, we show by overlay assays that E-FABP, immobilized on nitrocellulose, is able to capture S100A7 from cytosolic psoriatic protein extracts and vice versa, suggesting the formation of a complex between the two proteins. Using purified E-FABP and S100A7, the complex can be reconstituted only in presence of EDTA. Moreover, we show that increased EDTA concentrations in psoriatic cytosolic protein extracts enhance complex formation. Partial complex disruption was obtained by the addition of physiological concentrations of Zn2+ (0.1 mM), whereas Ca2+ at 5 mM and Mg2+ at 30 mM had no effect. On the other hand, high Ca2+ concentrations (30 mM) resulted in partial complex disruption. Oleic acid-binding properties were observed for free E-FABP and the complex E-FABP-S100A7, but not for free S100A7. By using confocal microscopy we show that S100A7 and E-FABP are co-localized in the cytoplasm of differentiating keratinocytes from lesional psoriatic skin. These data indicate that formation of the E-FABP-S100A7 complex and its FA-binding function might be regulated at least by bivalent cations.