KERATINOCYTE GROWTH-FACTOR AND KERATIN GENE-REGULATION

Keratinocyte growth factor (KGF) is a stromally derived paracrine mito gen that belongs to the fibroblast growth factor (FGF) family. It is s ecreted by dermal fibroblasts and specifically promotes keratinocyte p roliferation. We have recently shown that epidermal growth factor (EGF ) and transforming growth factor beta (TGF beta), modulators of kerati nocyte proliferation, regulate expression of specific keratin genes. H owever KGF, unlike EGF and TGF beta, allows keratinocytes to different iate normally. With this in mind, we sought to determine whether KGF m ay be involved in keratinocyte differentiation through a mechanism tha t does not involve regulation of keratin gene expression. We transfect ed human epidermal keratinocytes with ten different keratin gene promo ters linked to a reporter gene, and grew the transfected cells in the presence or absence of KGF. Interestingly, no significant change in ke ratin gene regulation was observed in the presence of KGF relative to control. The possibility that KGF influences the induction of keratin gene expression by other keratinocyte modulators, such as EGF, TGF bet a and gamma interferon (IFN gamma), was also explored. In these experi ments, the transformed keratinocytes were exposed simultaneously to KG F and another modulator. KGF did not significantly change the effects of EGF, TGF beta or IFN gamma on keratin gene expression. KGF's lack o f ability to directly regulate keratin gene expression suggests that K GF affects keratinocyte growth and differentiation through a pathway i ndependent of keratin gene regulation. These results illustrate that r egulation of keratinocyte proliferation can be separated from the regu lation of keratin gene expression. Furthermore, they indicate a profou nd difference in the functions of EGF and KGF signals: while both prom ote proliferation, EGF seems to be a mediator of an emergency response that involves induction of synthesis of keratins K6 and K16, e.g, in wound healing, whereas KGF seems to mediate a proliferative response c ompatible with normal differentiation that does not alter keratin gene expression.