¹Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park-Research Division, Smithville, TX, USA

Correspondence: Dr DG Johnson, Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park-Research Division, PO Box 389, Smithville, TX 78957, USA. E-mail: djohnson@mdanderson.org

²Current address: University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., IMC – Cardiology NB11.110, Dallas, TX 75390-8573, USA.

Received 7 June 2005; Revised 4 August 2005; Accepted 8 August 2005; Published online 3 October 2005.

Abstract

The E2F1 transcription factor, which is deregulated in most human cancers by mutations in the p16-cyclin D-Rb pathway, has both oncogenic and tumor-suppressive properties. This is dramatically illustrated by the phenotype of an E2F1 transgenic mouse model that spontaneously develops tumors in the skin and other epithelial tissues but is resistant to papilloma formation when subjected to a two-stage carcinogenesis protocol. Here, this E2F1 transgenic model was used to further explore the tumor-suppressive property of E2F1. Transgenic expression of E2F1 was found to inhibit ras-driven skin carcinogenesis at the promotion stage independent of the type of promoting agent used. E2F1 transgenic epidermis displayed increased expression of p19^ARF, p53, and p21^Cip1. Inactivation of either p53 or Arf in E2F1 transgenic mice restored sensitivity to two-stage skin carcinogenesis. While Arf inactivation impaired tumor suppression and p21 induction by E2F1, it did not reduce the level of apoptosis observed in E2F1 transgenic mice. Based on these findings, we propose that E2F1 suppresses ras-driven skin carcinogenesis through a nonapoptotic mechanism involving ARF and p53.