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Activation of ARF by oncogenic stress in mouse fibroblasts is independent of E2F1 and E2F2

Oncogene volume 21, pages 2939–2947 (2002)Cite this article

Abstract

The ARF tumour suppressor protein (p14ARF in human and p19ARF in mouse) is a major mediator of the activation of p53 in response to oncogenic stress. Little is known about the signalling pathways connecting oncogenic stimuli to the activation of ARF. Regulation of ARF occurs primarily at the transcriptional level and several modulators of ARF transcription have been identified. Notably, ectopic expression of E2F1 upregulates ARF transcriptionally, and both E2F1 and ARF have been implicated in apoptosis and cell-cycle arrest. We have used primary mouse fibroblasts deficient for E2F1, E2F2, or both to determine the possible role of these E2F proteins as upstream regulators of ARF in response to oncogenic stimuli and other stresses. In particular, we have studied the effects of oncogenic Ras and the viral oncoprotein E1A on ARF levels, neoplastic transformation, and sensitization to apoptosis. We have also examined the behaviour of the E2F-deficient MEFs with respect to immortalization and sensitivity to DNA damage. None of the ARF-mediated responses that we have analysed is significantly affected in E2F1−/−, E2F2−/− or E2F1/2−/− MEFs, and ARF is upregulated normally in all cases. Taken together, our results indicate that the activation of ARF in response to oncogenic stress can occur by E2F1- and E2F2-independent mechanisms. This challenges previous suggestions implicating E2F factors as key mediators in the activation of ARF by oncogenic stress.

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Acknowledgements

We are grateful to Charles Sherr for providing ARF−/− animals, to Miguel Campanero for critical reading of the manuscript, and to Itxaso García for animal handling at the UPV. This work was supported in part by grants from the Spanish Ministry of Education and the Human Frontier Science Program (to M Serrano), and the Spanish Ministry of Health and the Basque Department of Education (to A Zubiaga). M Murga is the recipient of a predoctoral fellowship from the Basque Government. The Department of Immunology and Oncology (DIO) was founded and is supported by the Spanish Council for Scientific Research (CSIC) and The Pharmacia Corporation.

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Authors and Affiliations

  1. Department of Immunology and Oncology, National Centre of Biotechnology, CSIC, Campus de Cantoblanco, Madrid, E-28049, Spain

    Ignacio Palmero & Manuel Serrano

  2. Department of Animal Biology and Genetics, Faculty of Sciences, University of the Basque Country, Campus de Leioa, Bilbao, E-48080, Spain

    Matilde Murga & Ana Zubiaga

  3. Institute of Molecular and Cellular Biology of Cancer, CSIC-University of Salamanca, Campus Miguel de Unamuno, Salamanca, E-37007, Spain

    Ignacio Palmero

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Correspondence to Manuel Serrano.

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Palmero, I., Murga, M., Zubiaga, A. et al. Activation of ARF by oncogenic stress in mouse fibroblasts is independent of E2F1 and E2F2. Oncogene 21, 2939–2947 (2002). https://doi.org/10.1038/sj.onc.1205371

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