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

E. E. Hoskins, R. W. Gunawardena, K. B. Habash, T. M. Wise-Draper, M. Jansen, E. S. Knudsen, S. I. Wells

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4798-4808
Number of pages11
JournalOncogene
Volume27
Issue number35
DOIs
StatePublished - Aug 14 2008

Fingerprint

Fanconi Anemia
Gene Expression
Fanconi Anemia Complementation Group Proteins
Genes
Genomic Instability
Chromatin Immunoprecipitation
Keratinocytes
HeLa Cells
DNA Damage
Neoplasms
Cell Cycle
Leukemia
Proteins
Up-Regulation
Down-Regulation
Bone Marrow
Skin
Mutation

Keywords

  • E2F
  • Fanconi anemia
  • Rb protein family
  • Transcription

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Hoskins, E. E., Gunawardena, R. W., Habash, K. B., Wise-Draper, T. M., Jansen, M., Knudsen, E. S., & Wells, S. I. (2008). Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway. Oncogene, 27(35), 4798-4808. https://doi.org/10.1038/onc.2008.121

Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway. / Hoskins, E. E.; Gunawardena, R. W.; Habash, K. B.; Wise-Draper, T. M.; Jansen, M.; Knudsen, E. S.; Wells, S. I.

In: Oncogene, Vol. 27, No. 35, 14.08.2008, p. 4798-4808.

Research output: Contribution to journalArticle

Hoskins, EE, Gunawardena, RW, Habash, KB, Wise-Draper, TM, Jansen, M, Knudsen, ES & Wells, SI 2008, 'Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway', Oncogene, vol. 27, no. 35, pp. 4798-4808. https://doi.org/10.1038/onc.2008.121
Hoskins EE, Gunawardena RW, Habash KB, Wise-Draper TM, Jansen M, Knudsen ES et al. Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway. Oncogene. 2008 Aug 14;27(35):4798-4808. https://doi.org/10.1038/onc.2008.121
Hoskins, E. E. ; Gunawardena, R. W. ; Habash, K. B. ; Wise-Draper, T. M. ; Jansen, M. ; Knudsen, E. S. ; Wells, S. I. / Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway. In: Oncogene. 2008 ; Vol. 27, No. 35. pp. 4798-4808.
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