SUPPRESSION OF CORNIFIED ENVELOPE FORMATION AND TYPE-1 TRANSGLUTAMINASE BY EPIDERMAL GROWTH-FACTOR IN NEOPLASTIC KERATINOCYTES

Epidermal growth factor (EGF) is a potent mitogen for keratinocytes. A lthough the role of the EGF receptor in cell proliferation has been ex tensively studied, the consequences of EGF receptor activation with re spect to cell differentiation remain less well characterized. Our stud ies demonstrate that stimulation of the EGF receptor substantially sup presses cellular differentiation in squamous cell carcinoma lines that overexpress the EGF receptor, as assessed by an EGF-dependent reducti on of cornified envelope formation. Only a modest ligand-dependent dec rease in cornified envelope formation was observed in normal keratinoc ytes. The response is dependent on the concentration of EGF and is evi dent after 1-2 days of EGF treatment. With extended EGF treatment; the messenger RNA levels for involucrin, a major structural component of the cornified envelope, were unaltered by EGF. In contrast, membrane-a ssociated transglutaminase enzyme activity, which predominantly repres ents type 1 (keratinocyte) transglutaminase, is markedly inhibited by EGF. The loss of type 1 transglutaminase activity is associated with r educed levels of the messenger RNA and protein. These studies suggest that the functional consequences of EGF receptor activation in squamou s cell carcinomas involve not only aberrant growth regulation, but, ad ditionally, reduction of terminal differentiation capacity.