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Genetics

Looking at the big picture

Nature Reviews Cancer volume 8, pages 486–487 (2008)Cite this article

It is thought that the main function of the tumour suppressor ARF (encoded by Cdkn2a ) is to activate p53 , but there is evidence to suggest other functions. Therefore, the authors used retroviral insertional mutagenesis in Arf- and Trp53-deficient, as well as wild-type, mice to identify genes that interacted with one of these tumour suppressors but not the other. A key component of their strategy was ensuring that they identified a large proportion of the mutations in each tumour, rather than just a fraction.

From the 510 tumours in 455 mice, the authors identified 10,806 independent insertions, and 346 loci in the genome were mutated significantly more often than expected by chance. These 'common insertion sites' included established oncogenes such as Myc, but also genes that had not previously been associated with cancer, such as the Notch receptor modulator Lunatic fringe. Of particular interest were the mutations that only occurred in one or two of the three genotypes. For example, several genes that are implicated in p53 signalling were mutated in Arf-deficient and wild-type backgrounds, but not in a Trp53-deficient one, implying that mutations in these genes are selected because they reduce p53 activity, or abrogate p53-dependent effects, something that is not necessary in a p53-null background.

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References

ORIGINAL RESEARCH PAPER

  1. Uren, A. G. et al. Large-scale mutagenesis in p19ARF- and p53-deficient mice identifies cancer genes and their collaborative networks. Cell 133, 727–741 (2008)

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FURTHER READING

  1. Sherr, C. J. Divorcing ARF and p53: an unsettled case. Nature Rev. Cancer 6, 663–673 (2006)

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Authors
  1. Patrick Goymer
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Goymer, P. Looking at the big picture. Nat Rev Cancer 8, 486–487 (2008). https://doi.org/10.1038/nrc2422

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