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E2F1 suppresses skin carcinogenesis via the ARF-p53 pathway

Oncogene volume 25, pages 867–876 (2006)Cite this article

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 p19ARF, p53, and p21Cip1. 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.

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Acknowledgements

We thank Jen Smith and Nancy Abbey for outstanding technical assistance; Dale Weiss, Lezlee Coghlan and co-workers for animal care; Irma Gimenez-Conti and co-workers for histology; Chris Brown and Joi Holcomb for artwork; Howard Thames for statistical analysis; and Shawnda Sanders for preparation of the manuscript. We also thank James DeGregori and Andriy Marusyk for helpful comments. This work was supported by grants from the National Institute of Health (CA79648 to DGJ, NIEHS center Grant ESO7784, and CA16672). JLR was supported in part by an American Legion Auxiliary Fellowship and training grant CA09480. TRB was supported by a Minority Postdoctoral Supplement from the Comprehensive Minority Biomedical Branch, NIH.

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  1. J L Russell

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

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

    J L Russell, R L Weaks, T R Berton & D G Johnson

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Correspondence to D G Johnson.

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Russell, J., Weaks, R., Berton, T. et al. E2F1 suppresses skin carcinogenesis via the ARF-p53 pathway. Oncogene 25, 867–876 (2006). https://doi.org/10.1038/sj.onc.1209120

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