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Cancer

Awakening angels

Nature volume 394, pages 616–617 (1998)Cite this article

When normal mammalian cells are subjected to stress signals — oxygen deficiency, radiation, DNA damage or chemotherapeutic drugs, for example — the ‘guardian of the genome’, p53, is woken up. Then, p53-dependent gene transcription is increased and ubiquitin-dependent degradation of the protein is blocked, all of which leads to the p53-mediated induction of programmed cell death and/or cell-cycle arrest. But how do such stress signals awaken p53? One idea is that stress-activated protein kinases modify p53, protecting it from degradation and activating its function as a transcription factor. In support of this theory, many phosphorylated forms of p53 are found in cells. Moreover, p53 can exist in a latent state that cannot bind DNA, and it can be released from this state by phosphorylation.

Enthusiasm for DNA-PK has, until now, been tempered by the finding that mice with severe combined immunodeficiency (SCID), which have a genetic defect in DNA-PK, can nevertheless respond to DNA damage in a p53-dependent manner3,4. Thus, attention shifted to other related protein kinases that can either directly or indirectly affect phosphorylation of p53. These include the ATM protein, which is defective in patients with ataxia telangiectasia (AT)5,6, and related ATR kinases.

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Figure 1: Possible ways to activate the p53 response.

O. LANE

Figure 2: Another model for activation of p53.

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  1. the Department of Biochemistry, Cancer Research Campaign Laboratories, University of Dundee, Dundee, DD1 4HN, UK

    David Lane

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Lane, D. Awakening angels. Nature 394, 616–617 (1998). https://doi.org/10.1038/29166

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