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Leukaemia

Wandering downstream

Nature Reviews Cancer volume 6, pages 576–577 (2006)Cite this article

Using an unbiased expression profiling screen, the authors identified MYC as a gene that is downregulated when Notch1 function is inhibited in T-ALL cells. Although MYC had previously been identified as a gene that is upregulated by the cleaved and active nuclear form of Notch1, ICN1, evidence that MYC was a direct target of Notch1 was lacking.

Generation of ICN1 involves two successive cleavages in Notch1, the second of which is mediated by a γ-secretase complex that can be blocked by γ-secretase inhibitors (GSIs). The authors used a T-ALL cell line that accumulates the initial cleaved form of Notch1 when it is treated with a reversible GSI. Upon washout of GSI, this partially activated form of Notch1 is rapidly converted to ICN1. The resulting pulse of ICN1 produced an increase in the transcription of MYC even when protein synthesis was inhibited, which indicates that the transcription of MYC is directly regulated by ICN1.

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References

ORIGINAL RESEARCH PAPER

  1. Weng, A. P. et al. c-Myc is an important target of Notch1 in T cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 17 July 2006 (doi: 10.1101/gad.1450406)

FURTHER READING

  1. Grabher, C., von Boehmer, H. & Look, A. T. Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nature Rev. Cancer 6, 347–359 (2006)

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Authors
  1. Nicola McCarthy
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McCarthy, N. Wandering downstream. Nat Rev Cancer 6, 576–577 (2006). https://doi.org/10.1038/nrc1965

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  • DOI: https://doi.org/10.1038/nrc1965

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