RETINOID REGULATION OF HEPARIN-BINDING EGF-LIKE GROWTH-FACTOR GENE-EXPRESSION IN HUMAN KERATINOCYTES AND SKIN

Retinoic acid (RA) has profound effects on epidermal homeostasis; howe ver, the molecular mechanisms by which retinoids regulate keratinocyte cell proliferation and differentiation are not well understood. Here we report that mRNA expression of heparin-binding EGF-like growth fact or (HB-EGF), a member of the EGF family of growth factors, is induced by RA in human keratinocytes and skin, and is overexpressed in the con text of epidermal hyperplasia in vivo. Treatment of normal adult human keratinocytes with micromolar concentrations of RA significantly indu ced the expression of HB-EGF The response was efficiently blocked by s pecific inhibitors of ErbB tyrosine kinase activity, MAP kinase kinase (MEK), or p38 stress-activated protein kinase. RA also enhanced the i nduction of HB-EGF mRNA in human skin organ culture, an ex vivo model system displaying many similarities to wound healing in vivo. HB-EGF t ranscripts were markedly increased in human skin by topical treatment with RA under conditions known to provoke epidermal hyperplasia. HB-EG F transcripts were also markedly overexpressed in the hyperplastic epi dermis of psoriatic lesions, relative to normal skin. These results su pport the hypothesis that the effects of RA on epidermal hyperplasia a re mediated at least in part by HB-EGF, and suggest that signal transd uction mechanisms other than or in addition to nuclear RA receptors co ntribute to this effect.