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Tumour suppressors

Discrimination

Nature Reviews Cancer volume 4, page 503 (2004)Cite this article

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Given that components of the ARF pathway are often mutated in tumours, the question of how Cdkn2a (which encodes ARF) is regulated is intriguing. Members of the E2F family of transcriptional promoters and repressors have been implicated. The Cdkn2a promoter has two E2F-binding sites and overexpression of E2F1 is sufficient to cause ARF expression, but direct regulation of Cdkn2a by E2F has not been shown. Previously Lees and co-workers showed that activation of E2F-responsive genes is impaired in mice deficient in the E2f3 -encoded proteins E2F3a and E2F3b. So, in this study the authors hypothesized that if ARF is regulated by E2F, its expression in this animal model should be reduced. Surprisingly, in mouse embryo fibroblasts (MEFs) derived from these animals, ARF was highly expressed with a concomitant increase in p53 activity.

So is Cdkn2a directly regulated by E2F family members? By using a combination of PCR after reverse transcription of RNA and chromatin immunoprecipitation (ChIP), the authors show that in asynchronously dividing normal MEFs, E2F3 binds to and represses the Cdkn2a promoter. Interestingly, in G0-arrested cells the splice variant E2F3b was largely involved in suppressing ARF expression, defining a repressive function for this protein.

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ORIGINAL RESEARCH PAPER

  1. Aslanian, A. et al. Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics. Genes Dev. 15 June 2004 (doi:10.1101/gad.1196704)

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Authors
  1. Nicola McCarthy
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McCarthy, N. Discrimination. Nat Rev Cancer 4, 503 (2004). https://doi.org/10.1038/nrc1407

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  • DOI: https://doi.org/10.1038/nrc1407

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