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Direct transcriptional regulation of MDM2 by Fli-1

Oncogene volume 24, pages 962–969 (2005)Cite this article

Abstract

The Ets transcription factor, Fli-1, has been shown to play a pivotal role in the induction and progression of Friend Murine Leukemia Virus (F-MuLV)-induced erythroleukemia, with its overexpression leading to erythroblast survival, proliferation, and inhibition of terminal differentiation. P53 inactivation is an additional genetic alteration that occurs in late-stage leukemic progression associated with in vivo and in vitro immortalization. Since p53 protein expression levels are low, to undetectable, in primary erythroleukemic cells that express elevated levels of Fli-1, we investigated the potential regulation of p53 by Fli-1. We assessed whether the overexpression of Fli-1 could partially regulate p53 via modulation of its well-established regulator, MDM2. In this paper, we demonstrate that the promoter of MDM2 contains a consensus binding site for Fli-1 that is bound by this transcription factor in vitro and in vivo, resulting in MDM2 transcriptional regulation. We further substantiate these observations in vivo by demonstrating a positive correlation in the expression of Fli-1 and MDM2, and a negative correlation with p53 in leukemic tissues obtained from mice with Friend Disease. These observations depict a significant function of Fli-1 overexpression in the indirect control of p53, evidently capable of leading to an increasingly aggressive erythroleukemic clone in vivo.

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Acknowledgements

We thank Drs Frank McCormick and Stefan Ries (University of California, USA) for generously providing the MDM2 reporter constructs. We also thank Ms Stacey Hunt for her help in the preparation of the manuscript and Drs Jorge Filmus, Michelle Anderson and Ms Christina Lee for helpful discussions and comments on the manuscript. This work was supported by a grant from the National Cancer Institute of Canada (NCIC) and Canadian Institute of Health Research (CIHR) to YB-D. AT and DC are supported by scholarships from the CIHR.

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Authors and Affiliations

  1. Department of Medical Biophysics, Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Ontario, Canada, M4N 3M5

    Amandine H L Truong, David Cervi & Yaacov Ben-David

  2. Division of Molecular and Cellular Biology, Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Ontario, Canada, M4N 3M5

    Amandine H L Truong, David Cervi, Jane Lee & Yaacov Ben-David

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  1. Amandine H L Truong
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Correspondence to Yaacov Ben-David.

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Truong, A., Cervi, D., Lee, J. et al. Direct transcriptional regulation of MDM2 by Fli-1. Oncogene 24, 962–969 (2005). https://doi.org/10.1038/sj.onc.1208323

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