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  • Review Article
  • Published:

p73: Friend or foe in tumorigenesis

Nature Reviews Cancer volume 2, pages 605–615 (2002)Cite this article

Key Points

  • The TP73 gene maps to a region (1p36.33) that is frequently deleted in neuroblastoma, indicating that loss of p73 function might have a role in the development of this tumour. However, mutations of TP73 are rare in human cancer.

  • p73 protein levels increase after DNA damage due to protein stabilization via a c-ABL-dependent pathway.

  • p53 seems to require p63 and p73 to induce apoptosis, indicating a very tight relationship between the three members of the same family.

  • The TP73 gene encodes two different proteins that are expressed under the control of two independent promoters, and that have opposite activities: the transcriptionally active full-length TAp73, and the amino-terminally truncated dominant-negative ΔNp73.

  • TAp73 induces cell-cycle arrest and apoptosis. Antithetically, ΔNp73 inhibits both TAp73- and p53-induced apoptosis. Furthermore, ΔNp73 is induced by TAp73 and p53, creating a dominant-negative feedback loop that regulates p53 and p73 function.

  • In keeping with its anti-apoptotic and potentially oncogenic role, ΔNp73 is an adverse prognostic marker for neuroblastoma patients. It would, therefore, seem that fine-tuning of TAp73 and ΔNp73 ratios within the individual cellular context dictates the functional outcome, and it comes as no surprise that enhanced expression of the ΔNp73 forms, rather than inactivating mutations within p73, is associated with cancer development.

Abstract

As p53 and its homologue p73 have significant sequence and functional similarities, p73 might also be expected to act as a tumour suppressor. However, p73 is activated after DNA damage in a way that is distinct from that of p53. The existence of ΔNp73 — an isoform of p73 that is encoded by a distinct promoter and that lacks the transactivation domain — further complicates matters. It seems to function as an oncogene by inhibiting both p73- and p53-induced apoptosis. So how can these opposing functions be reconciled in human tumours?

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Figure 1: The p53 family.
Figure 2: Isoforms of p73.
Figure 3: Regulation of ΔNp73 by p53 and TAp73.
Figure 4: Pathway involving p73 in DNA damage.
Figure 5: Molecular interactions of p73.

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Acknowledgements

We would like to thank R. A. Knight for stimulating discussion, critical suggestions and useful comments, and A. Oberst for discussions. The basic research discussed in the present report has been carried out thanks to the generous support of grants from Telethon, Aire, Mior, the EU and Min-Salute.

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Authors and Affiliations

  1. c/o Department of Experimental Medicine and Biochemical Sciences, Biochemistry Laboratory, IDI-IRCCS, University of Rome 'Tor Vergata', Rome, 00133, Italy

    Gerry Melino & Vincenzo De Laurenzi

  2. Regulation of Cell Growth Laboratory, National Cancer Institute, Frederick, 21702, Maryland, USA

    Karen H. Vousden

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  1. Gerry Melino
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  2. Vincenzo De Laurenzi
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  3. Karen H. Vousden
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Correspondence to Gerry Melino.

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FURTHER INFORMATION

The role of the p53 gene

The IARC TP53 Mutation Database

Glossary

p53

A protein that is expressed after DNA damage, and that mediates cell-cycle arrest and the induction of apoptosis. For its crucial role, it has been defined as the 'Guardian of the Genome'.

PROMOTER

A portion of the genome that controls the expression of a specific gene.

SPLICING

Mechanisms that control the maturation of RNA by excluding or including specific exons, thereby generating proteins that have different structures, and possibly different functions.

WAF1

A cyclin-dependent kinase inhibitor that arrests cells at the G1/S transition. It is induced by p53 after DNA damage to prevent the proliferation of cells that have genetic damage, and to allow the cell's DNA-repair machinery to repair the genome.

PUMA

A protein that belongs to the BCL2 family, and, in particular, to the BH3-only family of proteins. It is induced by p53 and p73 to trigger cell death.

DNA DAMAGE

Structural modification of the DNA nucleotides that results in aberrant function. It is induced by physical and chemical agents.

MISMATCH REPAIR

Base–base mismatches and insertion/deletion loops arise as a consequence of DNA-polymerase slippage during DNA synthesis. The mismatch-repair system corrects these, and is highly conserved between species and in humans. It requires at least six different proteins, and germ-line mutations of any of these genes give rise to hereditary non-polyposis colon cancer.

c-ABL

A non-receptor tyrosine kinase that inhibits entry into S phase by means of a p53- and retinoblastoma (RB)-dependent pathway. It is activated in response to DNA-damaging agents. Its kinase activity and transformation potential can be activated by: formation of the fusion protein BCR–ABL; deletion of the SH3 domain; hyperexpression; and amino-terminal deletions.

c-MYC

An oncogene that is a member of the helix–loop–helix/leucine-zipper superfamily. It forms heterodimers with MAX and binds specific DNA sequences known as E-box MYC sites. It is implicated in the control of normal proliferation and differentiation. Altered expression is involved in neoplastic transformation.

E1A

A family of adenovirus proteins that is derived by alternative splicing of the E1A gene. E1A proteins mediate transcriptional regulation of both viral and cellular genes to facilitate viral life, induce cell-cycle progression and lead to cellular transformation.

MDMX

MDMX, like MDM2, controls the stability of p53. Both proteins are induced by p53, and are able to bind p53 itself. They are E3 ubiquitin ligases that target p53 for degradation.

BECKWITH–WEIDEMANN SYNDROME

(BWS). A syndrome that is characterized by EXOMPHALOS, macroglossia (enlarged tongue) and gigantism (excessive linear growth) in the neonate. Patients have an increased risk of developing specific tumours. BWS is caused by a mutation in chromosome 11p15.5. The mode of inheritance is complex.

EXOMPHALOS

In an exomphalos, some of the abdominal contents are found outside the abdomen in a thin clear sac to which the baby's umbilical cord is attached. The sac consists of amnion and parietal peritoneum, with some mesenchyme in between.

CD95

The first identified death receptor. This membrane receptor activates apoptosis after binding of its ligand (CD95L).

NEUROBLASTOMA

The most frequent solid paediatric cancer. It is highly aggressive with fewer than 30% of children surviving.

LOSS OF HETEROZYGOSITY

(LOH). Loss of one of the genome's two copies of a given gene or genetic region.

POLYMORPHISM

Alteration of the sequence of DNA that does not affect its function.

CpG ISLAND

A region of DNA with a high density of cytosine–phospho-guanine (CpG) nucleotides, which are usually located in the promoter region or the first exons of a gene. CpG islands are involved in the regulation of transcription, because their methylation can lead to permanent silencing of the associated gene.

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Melino, G., De Laurenzi, V. & Vousden, K. p73: Friend or foe in tumorigenesis. Nat Rev Cancer 2, 605–615 (2002). https://doi.org/10.1038/nrc861

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