Functional regulation of p73 and p63: development and cancer

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Abstract

The transcription factor and tumour suppressor p53 and its two homologues p63 and p73 form a family of proteins. p63 and p73 show much greater molecular complexity than p53 because they are expressed both as multiple alternatively spliced C-terminal isoforms, and as N-terminally deleted, dominant-negative proteins that show reciprocal functional regulation. In addition, several other factors, such as post-translational modifications and specific and common family regulatory proteins, result overall in subtle modulation of their biological effects. Although all p53, p63 and p73 family members are regulators of the cell cycle and apoptosis, the developmental abnormalities of p73- and p63-null mice do not show enhanced tumour susceptibility of p53 knockouts, suggesting that complex regulatory processes modulate the functional effects of this family of proteins.

Section snippets

The p53 family: structure and interplay

The striking differences in function between p53, p73 and p63 revealed by gene deletion studies are unexpected because all three proteins have a similar basic domain structure and there is very high amino acid identity in the DNA-binding domain of all three proteins (Figure 1). Moreover, p53, p63 and p73 activate transcription of many of the same genes, such as p21 and Bax. However, this superficial similarity conceals a marked increase in the complexity of p63 and p73, largely owing to their

Functional regulation by cellular localization

The function of p73 and p63 can be regulated by (i) subcellular localization, (ii) post-translational modifications, and (iii) common and specific regulatory proteins, among other mechanisms. Therefore, the functional complexities implicit in the multiple isoforms of p63 and p73 (described earlier) are further compounded by combinations of these processes occurring in parallel within cells.

As transcription factors, nuclear localization of p53 and its family members is crucial for their

Post-translational modifications

Like p53 [7], the activities of p73 are also regulated by post-translational modifications (Figure 2a). The first identified example was phosphorylation of p73 by a non-receptor tyrosine kinase, c-Abl, at Tyr99 in response to DNA-damaging agents 28, 29, 30, which led to an increase in p73 stability [30]. Overexpression of c-Abl also induces phosphorylation of p73 on threonine residues adjacent to prolines, an effect that is blocked by dominant-negative inhibitors of p38 MAP kinase. p38 can also

Common regulators of the p53 family members

Several proteins are known to bind at least two p53 family members and influence their function (Table 1), although more studies are needed, particularly on p63-interacting proteins. Of those proteins regulating all p53 family members, the apoptosis-stimulating proteins of p53 (ASPP), ASPP1 and ASPP2 bind and selectively enhance the ability of the p53 family proteins to transactivate pro-apoptotic but not cell-cycle-related genes [35]. By contrast, the Wilms tumour 1 (WT1) group of isomeric

Specific regulators of p63 or p73

In addition to these common regulators that interact with at least two p53 family members, others appear to act selectively on either p63 or p73 (although this specificity requires rigorous confirmation), and other specific regulatory proteins will no doubt be identified using proteomic technology. One apparently specific regulator, the mismatch-repair protein PMS2, influences p73 activity by affecting its stability in the same way as mdm2 regulates p53. However, in this case, PMS2 stabilizes

Regulation of p63 reveals a complex C-terminal regulatory region

The C terminus of p63 contains a transactivation inhibitory (TI) domain that is able to physically bind and regulate the TA, creating an intramolecular regulatory mechanism 51, 52, and the splicing isoforms lacking this region (β, γ) have stronger transactivating activity. ΔNp63 also has intrinsic transcriptional activity owing to a second TA domain (TA2) (Figure 2). ΔNp63 can also form complexes with the TA isotypes, increasing their stability while keeping them inactive [51]. According to

A role for p73 in cell-cycle regulation, senescence and apoptosis

T cells from p73-deficient animals are resistant to apoptosis induced by T-cell receptor ligation [14], suggesting that TA isoforms are required for apoptosis induction in some tissues. Apoptosis induced by TCR activation is dependent on late G1 cell-cycle arrest, and is inhibited by dominant-negative E2F-1. These data therefore suggest that, like p53, p73 isoforms might act as regulators of both apoptosis and cell-cycle progression, although their role in these processes is less

Cancer chemotherapeutic drugs induce p73

Although p73 was initially reported not to be inducible by ultra-violet radiation [1], recent work has shown that p73 is induced by cisplatin [30] and doxorubicin [34]. A range of other chemotherapeutic drugs, including taxol, etoposide, camptothecin, gemcitabine and melphalan, also induce p73 and activate p73-dependent downstream gene expression and apoptosis 21, 66. Furthermore, inhibition of p73 function by dominant-negative p73 variants or small interfering RNA (siRNA) reduces the

Cancer or development?

Involvement of the p53/p63/p73 family in cancer and development must be evolutionarily conserved (Figure 4b). Although cancer and development might superficially seem very different biological processes, there is a unifying mechanistic principle underlying both, and that is apoptosis. Maturation of the nervous system and development of the cornified envelope of the skin both depend on regulated cell death. Therefore, the developmental phenotype of p73- and p63-null mice could possibly reflect

Future perspectives

It is clear that the phenotypic consequences of the expression of p53 family members are strongly conditioned by several other as-yet unidentified factors. This complexity leads to great plasticity in the repertoire of p53 family responses, and it could be anticipated that further subtleties of response remain to be elucidated. In addition, several important questions remain unresolved. For example, the induction of ΔNp73 isoforms by p53 and TAp73 makes little apparent biological sense unless

Acknowledgements

We thank Vincenzo De Laurenzi, Eleonora Candi, Mario Rossi and Eliana Munarriz for helpful comments and suggestions. The work was supported by grants from the Medical Research Council (to G.M.), Telethon (E872, E1224), AIRC, EU (QLG1-1999-00739 and QLK-CT-2002-01956), MIUR, MinSan (to G.M.) and the Ludwig Institute for Cancer Research (to X.L. and T.C.). We apologize to those authors whose relevant work could not be cited owing to space restrictions.

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