Keratinocyte growth factor and keratin gene regulation

Abstract

Keratinocyte growth factor (KGF) is a stromally derived paracrine mitogen that belongs to the fibroblast growth factor (FGF) family. It is secreted by dermal fibroblasts and specifically promotes keratinocyte proliferation. We have recently shown that epidermal growth factor (EGF) and transforming growth factor beta (TGFβ), modulators of keratinocyte proliferation, regulate expression of specific keratin genes. However KGF, unlike EGF and TGFβ, allows keratinocytes to differentiate normally. With this in mind, we sought to determine whether KGF may be involved in keratinocyte differentiation through a mechanism that does not involve regulation of keratin gene expression. We transfected human epidermal keratinocytes with ten different keratin gene promoters linked to a reporter gene, and grew the transfected cells in the presence or absence of KGF. Interestingly, no significant change in keratin 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, TGFβ and gamma interferon (IFBγ), was also explored. In these experiments, the transformed keratinocytes were exposed simultaneously to KGF and another modulator. KGF did not significantly change the effects of EGF, TGFβ or IFNγ on keratin gene expression. KGF's lack of ability to directly regulate keratin gene expression suggests that KGF affects keratinocyte growth and differentiation through a pathway independent of keratin gene regulation. These results illustrate that regulation of keratinocyte proliferation can be separated from the regulation of keratin gene expression. Furthermore, they indicate a profound difference in the functions of EGF and KGF signals: while both promote 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 compatible with normal differentiation that does not alter keratin gene expression.