Regulation of the differentiation-related gene Drg-1 during mouse skin carcinogenesis

Differentiation-related gene-1 (Drg-1) has been identified as a gene whose expression is increased in several processes related to differentiation, bu t its function is currently unknown. In this report, we show that Drg-1 was expressed in keratinocytes, this expression being rapidly increased as a r esult of induction by 12-O-tetradecanoylphorbol-13-acetate (TPA) or the pre sence of an activating form of Ha-ras. Induction by TPA occurred both in cu ltured cell lines and primary keratinocytes as well as in mouse skin after a single TPA application. Overexpression of Drg-1 was also observed in TPA- induced hyperplastic skin. In agreement, mouse skin papillomas and carcinom as also overexpressed Drg-1. In addition, Drg-1 was induced when keratinocy tes were forced to differentiate by calcium switch or serum starvation. Ana lysis of the expression of Drg-1 during the keratinocyte cell cycle demonst rated relatively high levels of Drg-1 mRNA in G(0), which increased in earl y G(1) and decreased afterwards in late G(1)/S. In situ analysis showed an accumulation of Drg-1 in the suprabasal layers of the skin, as well as in t he more differentiated areas of mouse skin papillomas. These results sugges t that, in addition to being upregulated during keratinocyte differentiatio n, the Drg-1 gene might have a complex function in skin tumorigenesis. (C) 2001 Wiley-Liss, Inc.