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  • Review Article
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The expanding universe of p53 targets

Key Points

  • p53 is a key tumour suppressor and master regulatory transcription factor that is altered in most human cancers. Several stresses lead to p53 activation, which results in various biological outcomes, including cell cycle arrest and apoptosis. Each of these events seems to contribute to tumour suppression. The p53 network can be affected by variation in p53 levels and the variety of genes targeted.

  • The extent of p53 transactivation and transcriptional repression is influenced by many factors, including p53 levels, cofactors and the specific response element (RE) sequences, all of which contribute to the role that p53 has in the aetiology of cancer. Cooperativity in cis between p53 and other transcription factors, such as oestrogen receptors, in the activation of canonical and non-canonical REs greatly expands the p53 master regulatory network.

  • Essential components in the p53-mediated transactivation of target genes are the p53 RE sequences, which differ individually from the consensus sequence and support p53 transactivation to varying extents. Transactivation assays developed in budding yeast and human cells have been valuable tools for defining and assessing the p53 transcriptional functionality of potential RE targets.

  • Non-canonical sequences that differ significantly from consensus can also support transactivation by p53, thereby greatly expanding the p53 transcriptional network. Canononical and non-canonical p53 REs can be transactivated by several p53 mutants with altered functionality, many of which are associated with cancer.

  • Using information about the functionality of p53 REs, it seems that in the evolution of humans and primates many DNA metabolism and repair genes have evolved to become responsive to p53 through the inclusion of functional p53 REs.

Abstract

The p53 tumour suppressor is modified through mutation or changes in expression in most cancers, leading to the altered regulation of hundreds of genes that are directly influenced by this sequence-specific transcription factor. Central to the p53 master regulatory network are the target response element (RE) sequences. The extent of p53 transactivation and transcriptional repression is influenced by many factors, including p53 levels, cofactors and the specific RE sequences, all of which contribute to the role that p53 has in the aetiology of cancer. This Review describes the identification and functionality of REs and highlights the inclusion of non-canonical REs that expand the universe of genes and regulation mechanisms in the p53 tumour suppressor network.

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Figure 1: Many factors affect p53-dependent transcriptional modulation and the universe of directly targeted genes.
Figure 2: Cooperation in cis between p53 and other master regulators to drive transactivation at canonical and non-canonical p53 REs.

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Acknowledgements

This work was supported by intramural research funds from the National Institute of Environmental Health Sciences project 1 Z01 ES065079 (to D.M. and M.A.R.) and partially supported by the Italian Association for Cancer Research (to A.I.).

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Supplementary information

Supplementary information S1

Rules for assessing functionality of p53 response elements Presented are rules derived from experimental results obtained using yeast- and mammalian based functional assays1–6, in which > 60 different p53 response elements (REs) were tested. (PDF 234 kb)

Supplementary information S2

Examples of noncanonical p53 REs from validated targets* (PDF 170 kb)

Supplementary information S3

Novel validated p53 REs that differ widely from consensus* (PDF 164 kb)

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Menendez, D., Inga, A. & Resnick, M. The expanding universe of p53 targets. Nat Rev Cancer 9, 724–737 (2009). https://doi.org/10.1038/nrc2730

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