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ASPPs and cancer

Nature Reviews Cancer volume 6, pages 217–226 (2006)Cite this article

An Erratum to this article was published on 01 May 2006

Key Points

  • The p53-dependent apoptotic pathway is central to tumour prevention and is consistently disrupted in malignancy; disruption can occur in p53 itself or in any of its cofactors or target genes.

  • The members of the ASPP (ankyrin-repeat-, SH3-domain- and proline-rich-region-containing protein) family have been identified as specific regulators of p53-, p63- and p73-mediated apoptosis. The family comprises three members of which two, ASPP1 and ASPP2, are pro-apoptotic and the third, inhibitory iASPP (iASPP), is anti-apoptotic. The importance of the ASPP family in regulating p53 function is supported by the genetic evidence that C. elegans iASPP is an inhibitor of p53 and can also inhibit the function of human p53 in human cells as effectively as humn iASPP.

  • The ASPP family is characterized by a highly conserved carboxyl terminus — ankryin repeats, SH3 (Src homology 3) domain and proline-rich region — which is the preferred binding site for its partners, including the tumour suppressor p53, BCL2, RELA/p65, protein phosphatase 1, YES-associated protein and adenomatosis polyposis coli 2. The amino terminus is conserved only in the pro-apoptotic members, ASPP1 and ASPP2.

  • ASPP expression levels correlate with cellular sensitivity (ASPP1 and ASPP2 increase sensitivity) and resistance (iASPP increases resistance) to apoptosis. Deregulation of ASPP expression has been reported in several different cancers, underlining their importance in tumour development. The members of the ASPP family might be new molecular targets for cancer therapy.

Abstract

One of the most frequently mutated genes in human cancers, tumour suppressor p53 (TP53), can induce cell-cycle arrest and apoptosis. The apoptotic function of p53 is tightly linked to its tumour-suppression function and the efficacy of many cancer therapies depends on this. The identification of a new family of proteins, known as ASPPs (ankyrin-repeat-, SH3-domain- and proline-rich-region-containing proteins), has led to the discovery of a novel mechanism that selectively regulates the apoptotic function, but not the cell-cycle-arrest function, of p53, and gives an insight into how p53 responds to different stress signals. ASPPs might be new molecular targets for cancer therapy.

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Figure 1: The human ASPP family: chromosomal location and splice-variant structure.
Figure 2: A selection of ASPP orthologues.
Figure 3: ASPP function in cellular apoptotic pathways.

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Acknowledgements

We would like to thank S. Barnsley for her critical reading of this manuscript and also all members of X.L.'s laboratory. This work is funded by the Ludwig Institute for Cancer Research.

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  1. Ludwig Institute for Cancer Research, Courtauld Building, 91 Riding House Street, London, W1W 7BS, UK

    Giuseppe Trigiante & Xin Lu

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Correspondence to Xin Lu.

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Glossary

Ankyrin repeat

Short motif (about 30 amino acids) that is found in many proteins, usually in two or more repeats. Ankyrin repeats mediate protein interactions.

SH3 domain

Conserved protein motifs of about 50 amino acids that mediate interactions with proline-rich regions on partner proteins.

Proline-rich region

Protein motif that is characterized by the recurrence of the proline residue in the form PXXP where X is any amino acid. Proline-rich regions mediate protein–protein interactions, particularly to SH3 domains.

Chromatin immunoprecipitation

A sensitive molecular-biology technique that is used to quantify the binding of protein to specific DNA sequences.

Orthologues

Proteins from different organisms that share function and often sequence similarity, and are thought to be evolutionarily related.

RNA interference

A gene-silencing technique that was originally discovered and used in C. elegans. When exposed to short double-stranded RNA sequences that have been taken from mRNAs, this organism ingests them and inactivates expression of the corresponding gene.

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Trigiante, G., Lu, X. ASPPs and cancer. Nat Rev Cancer 6, 217–226 (2006). https://doi.org/10.1038/nrc1818

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