Trends in Biochemical Sciences
Functional regulation of p73 and p63: development and cancer
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.
References (73)
Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers
Cell
(1997)p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities
Mol. Cell
(1998)Induction of neuronal differentiation by p73, in a neuroblastoma cell line
J. Biol. Chem.
(2000)On the shoulders of giants: p63, p73 and the rise of p53
Trends Genet.
(2002)Akt phosphorylates the yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis
Mol. Cell
(2003)p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis
Cancer Cell
(2003)Nuclear import and export signals in control of the p53-related protein p73
J. Biol. Chem.
(2002)Exclusion of c-Abl from the nucleus restrains the p73 tumor suppression function
J. Biol. Chem.
(2003)Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle dependent manner and negatively regulate p73
J. Biol. Chem.
(2003)DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target genes
Mol. Cell
(2002)
ASPP proteins specifically stimulate the apoptotic function of p53
Mol. Cell
Physical interaction between Wilms tumor 1 and p73 proteins modulates their functions
J. Biol. Chem.
MDM2 and MDMX bind and stabilize the p53-related protein p73
Curr. Biol.
The human MDM2 oncoprotein increases the transcriptional activity and the protein level of the p53 homolog p63
J. Biol. Chem.
HMGB1 and HMGB2 cell-specifically down-regulate the p53- and p73-dependent sequence-specific transactivation from the human Bax gene promoter
J. Biol. Chem.
p73 interacts with c-Myc to regulate Y-box-binding protein-1 expression
J. Biol. Chem.
Physical interaction of p73 with c-Myc and MM1, a c-Myc-binding protein, and modulation of the p73 function
J. Biol. Chem.
ΔNp63 induces β-catenin nuclear accumulation and signalling
Cancer Cell
E2F and cell cycle control: a double edged sword
Arch. Biochem. Biophys.
Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
Cell
Chemosensitivity linked to p73 function
Cancer Cell
Oncogenes induce and activate endogenous p73 protein
J. Biol. Chem.
Mutations in the p53 homolog p63: allele-specific developmental syndromes in humans
Trends Mol. Med.
p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours
Nature
p73 is required for survival and maintenance of CNS neurons
J. Neurosci.
p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development
Nature
p63 is a p53 homologue required for limb and epidermal morphogenesis
Nature
Live or let die: the cell's response to p53
Nat. Rev. Cancer
p73: friend or foe in tumorigenesis
Nat. Rev. Cancer
Two new p73 splice variants, γ and δ, with different transcriptional activity
J. Exp. Med.
Additional complexity in p73: induction by mitogens in lymphoid cells and identification of two new splicing variants e and z
Cell Death Differ.
Role for the p53 homologue p73 in E2F-1-induced apoptosis
Nature
A common polymorphism acts as an intragenic modifier of mutant p53 behaviour
Nat. Genet.
Human ΔNp73 regulates a dominant negative feedback loop for TA p73 and p53
Cell Death Differ.
Differential regulation of p63 and p73 expression
Oncogene
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