Deregulated expression of DP1 induces epidermal proliferation and enhances skin carcinogenesis.

Abstract

E2F transcription factors have been implicated in several cellular processes, including proliferation, apoptosis, and oncogenic transformation. A functional E2F factor consists of a heterodimer containing an E2F polypeptide (E2F1-E2F6) and a DRTF1-polypeptide (DRTF1-polypeptide-1 (DP1) or DRTF1-polypeptide-2). It is the E2F subunit that supplies the transcriptional activation domain and the motif involved in binding to members of the retinoblastoma tumor suppressor family. The role of the DP subunit in regulating E2F-dependent activities is not completely understood. To examine the properties of DP1 in vivo, we generated transgenic mouse lines expressing DP1 under the control of a keratin 5 (K5) promoter. Overexpression of DP1 in basal layer keratinocytes caused mild hyperplasia and hyperproliferation of the epidermis but did not result in increased apoptosis or spontaneous tumor development. Coexpression of DP1 with E2F1 or E2F4 in the epidermis of bigenic mice modestly enhanced proliferation and apoptosis over the levels induced by E2F1 or E2F4 expression alone. In a two-stage chemical carcinogenesis assay, more and larger skin tumors developed in K5 DP1 transgenic mice than in nontransgenic mice. These findings show that in this in vivo model, deregulated expression of DP1 on its own induced proliferation and enhanced carcinogenesis.