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Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

Oncogene volume 27, pages 4798–4808 (2008)Cite this article

Abstract

Fanconi anemia (FA) is a genome instability syndrome that is characterized by progressive bone marrow failure and a high risk of cancer. FA patients are particularly susceptible to leukemia as well as squamous cell carcinomas (SCCs) of the head and neck, anogenital region and skin. Thirteen complementation groups and the corresponding FA genes have been identified, and their protein products assemble into nuclear core complexes during DNA-damage responses. Much progress has been made in our understanding of post-translational FA protein modifications and physical interactions. By contrast, little is known about the control of protein availability at the level of transcription. We report here that multiple FA proteins were downregulated during the proliferative arrest of primary human keratinocytes and HeLa cells, and that the observed regulation was at a transcriptional level. Proliferative stimuli such as expression of HPV16 E7 as well as E2F1 overexpression in primary cells resulted in coordinate FA upregulation. To define the underlying mechanism, we examined the endogenous FANCD2 promoter, and detected regulated binding of members of the E2F/Rb family in chromatin immunoprecipitation assays. Finally, a 1 kb promoter fragment was sufficient to confer E2F/Rb regulation in reporter assays. Taken together, our data demonstrate FA gene co-regulation in synchrony with the cell cycle and suggest that deregulated expression of individual FA genes—in addition to FA gene mutation—may promote FA-related human cancer.

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Acknowledgements

We thank Paul Andreassen, Ruhikanta Meetei, Qishen Pang, James Mulloy, Harmut Geiger, Yi Zheng and David Williams for helpful discussions and critical comments on the paper. We thank Jennifer Higginbotham for excellent technical assistance. We are grateful to Paul Lambert for providing NIKs and J23T3 cells and expert advice, as well as to James Lessard for the monoclonal actin antibody. We are grateful to Denise Galloway for the HPV16 E6 and E7 retroviral vectors. We thank Maureen Hoatlin for FANCA antibodies, and the Fanconi Anemia Research Fund for FANCC and FANCG antibodies. Vector supernatant was provided by the CCHMC Viral Vector Core and Translational Trials Development and Support Lab. This research was supported by Public Health Service grant CA102357, a grant from the Translational Research Initiative at CCHMC and a grant from the Fanconi Anemia Research Fund to SIW, and CA104213 to ESK.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    E E Hoskins, K B Habash, T M Wise-Draper & S I Wells

  2. Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    R W Gunawardena & E S Knudsen

  3. Department of Pediatrics, Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    M Jansen

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  1. E E Hoskins
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  2. R W Gunawardena
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  3. K B Habash
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Correspondence to S I Wells.

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Hoskins, E., Gunawardena, R., Habash, K. et al. Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway. Oncogene 27, 4798–4808 (2008). https://doi.org/10.1038/onc.2008.121

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