p63 and p73: p53 mimics, menaces and more

Article metrics

Abstract

Inactivation of the tumour suppressor p53 is the most common defect in cancer cells. The discovery of its two close relatives, p63 and p73, was therefore both provocative and confounding. Were these new genes tumour suppressors, p53 regulators, or evolutionary spin-offs? Both oncogenic and tumour-suppressor properties have now been attributed to the p53 homologues, perhaps reflecting the complex, often contradictory, protein products encoded by these genes. p63 and p73 are further implicated in many p53-independent pathways, including stem-cell regeneration, neurogenesis and sensory processes.

Key Points

  • Less than five years ago, the tumour suppressor p53 was thought to be one of a kind, but the discovery of two related gene products, p63 and p73, raised the possibility that the genome has more than one guardian.

  • All three genes encode transcription factors with an amino-terminal transactivation domain, a central DNA-binding domain and an oligomerization domain.

  • The gene structures encoding p63 and p73 are more complex than that of p53, with two promoters each giving rise to isotypes of opposing functions. In addition, several splicing events contribute to the diversity of p63 and p73 isotypes.

  • These fall into two broad categories: transactivating (TA) isoforms that resemble p53, and ΔN isoforms that are dominant-negative inhibitors of transcription. The ΔN isoforms explain why p63 and p73 can have oncogenic, as well as tumour-suppressor characteristics.

  • Both the TA and ΔN forms have three possible carboxyl termini, and these isoforms are termed α, β and γ. The α isoforms have two domains not present in p53: a steric α-motif (SAM, thought to be involved in protein?protein interactions) and a post-SAM domain whose function is a mystery.

  • Knockout mice have revealed functions for p63 and p73 that go beyond protecting the genome: p63 seems to control the balance of proliferation versus differentiation of epithelial stem cells, whereas p73 seems to be involved in fluid dynamics, neurogenesis and social behaviour.

  • An important question, which could shed light on the our understanding of their function, is which of these three genes evolved first?

  • Equally important is understanding how p63 and p73 control the processes of epithelial stem cell identity, neurogenesis, and secretion regulation, and the respective roles of the apparently contradictory isotypes in these events.

  • Finally, what are the genetic and physical interactions among p53 family members and do they collaborate or clash in mechanisms of tumour suppression?

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Gene structure of TP63/TP73.
Figure 3: ΔN isotypes are predominantly expressed in vivo.
Figure 4: Epithelial defects in p63-deficient mice: hints for a role in stem-cell regeneration?
Figure 2: Dual mechanism of inhibition by ΔN p63/p73 isotypes.

References

  1. 1

    Levine, A. p53, the cellular gatekeeper for growth and division. Cell 88, 323?331 (1997).

  2. 2

    Steele, R. J., Thompson, A. M., Hall, P. A. & Lane, D. P. The p53 tumour suppressor gene. Br. J. Surg. 85, 1460?1467 (1998).

  3. 3

    Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215? 221 (1992).

  4. 4

    Jacks, T. et al. Tumour spectrum analysis in p53-mutant mice. Curr. Biol. 4, 1?7 ( 1994).

  5. 5

    Lowe, S. W. Activation of p53 by oncogenes. Endocr. Relat. Cancer 6, 45?48 (1999).

  6. 6

    Kaghad, M. et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90, 809?819 ( 1997).Reports the discovery of the first p53 homologue, p73, and shows that p73 can transactivate p53 reporter genes and inhibit colony formation on transfection. p73 is shown to be lost in many neuroblastoma and other tumour cell lines, whereas the remaining allele is shown to be wild type and frequently overexpressed.

  7. 7

    Yang, A. et al. p63, a p53 homologue at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol. Cell 2, 305?316 ( 1998).Reports the discovery of second p53 homologue, p63, and defines the six principal transcripts derived from this gene. The dominant-negative action of the ΔN isoforms is also described.

  8. 8

    Augustin, M., Bamberger, C., Paul, D. & Schmale, H. Cloning and chromosomal mapping of the human p53-related KET gene to chromosome 3q27 and its murine homologue Ket to mouse chromosome 16. Mamm. Genome 9, 899?902 (1998).

  9. 9

    Osada, M. et al. Cloning and functional analysis of human p51, which structurally and functionally resembles p53. Nature Med. 4, 839?843 (1998).Details the cloning of one of the isotypes of p63, and describes the general absence of mutations in this gene in a large number of tumour-derived cell lines.

  10. 10

    Hibi, K. et al. AIS is an oncogene amplified in squamous cell carcinoma. Proc. Natl Acad. Sci. USA 97, 5462? 5467 (2000).

  11. 11

    Jost, C. A., Marin, M. C. & Kaelin, W. G. Jr p73 is a simian [correction of human] p53-related protein that can induce apoptosis. Nature 389, 191?194 (1997). Describes the ability of p73 to induce apoptosis when expressed in established cell lines.

  12. 12

    Zhu, J., Jiang, J., Zhou, W. & Chen, X. The potential tumor suppressor p73 differentially regulates cellular p53 target genes. Cancer Res. 58, 5061?5065 (1998).

  13. 13

    Di Como, C. J., Gaiddon, C. & Prives, C. p73 function is inhibited by tumour-derived p53 mutants in mammalian cells. Mol. Cell. Biol. 19, 1438?1449 (1999).

  14. 14

    Shimada, A. et al. The transcriptional activities of p53 and its homologue p51/p63: similarities and differences. Cancer Res. 59, 2781?2786 (1999).

  15. 15

    Ishida, S., Yamashita, T., Nakaya, U. & Tokino, T. Adenovirus-mediated transfer of p53-related genes induces apoptosis of human cancer cells. Jpn. J. Cancer Res. 91, 174 ?180 (2000).

  16. 16

    Levrero, M. et al. The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J. Cell Sci. 113, 1661?1670 (2000).

  17. 17

    Yang, A. et al. p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404, 99?103 (2000).The phenotype of the p73 knockout mouse is described. The TP73 gene is also shown to resemble the overall structure of the TP63 gene, and to produce both ΔN and TA isotypes.

  18. 18

    Ponting, C. P. SAM: A novel motif in yeast sterile and Drosophila polyhomeotic proteins . Protein Sci. 4, 1924? 1930 (1995).

  19. 19

    Chi, S. W., Ayed, A. & Arrowsmith, C. H. Solution structure of a conserved carboxy?terminal domain of p73 with structural homology to the SAM domain. EMBO J. 18, 4438?4445 ( 1999).

  20. 20

    De Laurenzi, V. et al. Two new p73 splice variants, γ and δ, with different transcriptional activity. J. Exp. Med. 188, 1763?1768 (1998).

  21. 21

    Ozaki, T. et al. Deletion of the COOH-terminal region of p73α enhances both its transactivation function and DNA-binding activity but inhibits induction of apoptosis in mammalian cells. Cancer Res. 59, 5902?5907 (1999).

  22. 22

    Gong, J. G. et al. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399, 806?809 (1999).

  23. 23

    Agami, R., Blandino, G., Oren, M. & Shaul, Y. Interaction of c-Abl and p73α and their collaboration to induce apoptosis. Nature 399, 809?813 ( 1999).

  24. 24

    Yuan, Z. M. et al. p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature 399, 814? 817 (1999).

  25. 25

    White, E. & Prives, C. DNA damage enables p73. Nature 399, 734?735 ( 1999).

  26. 26

    Ongkeko, W. M. et al. MDM2 and MDMX bind and stabilize the p53-related protein p73 . Curr. Biol. 9, 829?832 (1999).

  27. 27

    Balint, E., Bates, S. & Vousden, K. H. Mdm2 binds p73α without targeting degradation . Oncogene 18, 3923?3929 (1999).

  28. 28

    Zeng, X. et al. MDM2 suppresses p73 function without promoting p73 degradation . Mol. Cell. Biol. 19, 3257? 3266 (1999).

  29. 29

    Zeng, X. et al. The amino-terminal domain of p73 interacts with the CH1 domain of p300/CREB binding protein and mediates transcriptional activation and apoptosis . Mol. Cell. Biol. 20, 1299? 1310 (2000).

  30. 30

    Sherr, C. J. & Weber, J. D. The ARF/p53 pathway. Curr. Opin. Genet. Dev. 10, 94?99 (2000).

  31. 31

    Scharnhorst, V., Dekker, P., van der Eb, A. J. & Jochemsen, A. G. Physical interaction between Wilms tumour 1 and p73 proteins modulates their functions. J. Biol. Chem. 275, 10202? 10211 (2000).

  32. 32

    Marin, M. C. et al. A common polymorphism acts as an intragenic modifier of mutant p53 behaviour. Nature Genet. 25, 47? 54 (2000).An intriguing paper that proposes a mechanism of p73 inactivation by mutations in p53.

  33. 33

    Herranz, M., Santos, J., Salido, E., Fernandez-Piqueras, J. & Serrano, M. Mouse p73 gene maps to the distal part of chromosome 4 and might be involved in the progression of γ-radiation-induced T-cell lymphomas. Cancer Res. 59, 2068? 2071 (1999).

  34. 34

    Ikawa, S., Nakagawara, A. & Ikawa, Y. p53 family genes: structural comparison, expression and mutation. Cell Death Differ. 6, 1154 ?1161 (1999).

  35. 35

    Han, S. et al. Infrequent somatic mutations of the p73 gene in various human cancers . Eur. J. Surg. Oncol. 25, 194? 198 (1999).

  36. 36

    Corn, P. G. Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt's lymphoma is associated with 5′ CpG island methylation . Cancer Res. 59, 3352? 3356 (1999).

  37. 37

    Kawano, S. et al. Loss of p73 gene expression in leukemias/lymphomas due to hypermethylation. Blood 94, 1113? 1120 (1999).

  38. 38

    Lissy, N. A., Davis, P. K., Irwin, M., Kaelin, W. G. & Dowdy, S. F. A common E2F-1 and p73 pathway mediates cell death induced by TCR activation Nature 407, 642?645 (2000).An interesting report that presents a role for p73 in the p53-independent process of activation-induced T-cell death.

  39. 39

    Irwin, M. et al. Role for the p53 homologue p73 in E2F-1-induced apoptosis. Nature 407, 645?648 ( 2000).The mechanistic details of the involvement of p73 in E2F-1 induced cell death, with particular relevance to Ref. 38 , are reported.

  40. 40

    Yang, A. et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714?718 (1999).Presents the phenotype of the TP63 knockout mouse. The authors conclude that these defects are not due to defects in commitment or differentiation of these tissues and structures, but rather a failure to maintain the regenerative stem cells.

  41. 41

    Mills, A. A. et al. p63 is a p53 homologue required for limb and epidermal morphogenesis . Nature 398, 708?713 (1999).Details the phenotype of the TP63 knockout mouse, and concludes that the underlying defect is a generalized failure in epithelial differentiation.

  42. 42

    Celli, J. et al. Heterozygous germline mutations in the p53 homologue p63 are the cause of EEC syndrome. Cell 99, 143? 153 (1999).The positional cloning of mutations responsible for EEC syndrome, a dominant disease affecting limb and craniofacial development and associated with ectodermal dysplasia. These mutations are in the TP63 gene, at residues corresponding to those mutated in TP53 in tumours. This report also describes how such mutant proteins might act in a dominant manner to inhibit wild-type p63 function.

  43. 43

    Pozniak, C. D. et al. An anti-apoptotic role for the p53 family member, p73, during developmental neuron death. Science 289, 304?306 (2000).Analysis of sympathetic ganglia of TP73 knockout mice reveals a 50% reduction of neurons, which die in the absence of nerve growth factor in a p53-dependent manner. ΔN-p73, the main p73 product in sympathetic neurons of wild-type animals, is shown to have the capacity to prevent cell death after nerve growth factor withdrawal, and therefore to function potentially in a dominant-negative manner towards p53.

  44. 44

    Weinberg, W. C., Azzoli, C. G., Chapman, K., Levine, A. J. & Yuspa, S. H. p53-mediated transcriptional activity increases in differentiating epidermal keratinocytes in association with decreased p53 protein. Oncogene 10, 2271? 2279 (1995).This paper details unusual activities of p53 in keratinocyte development that now may be relevant to p63 function.

  45. 45

    Parsa, R., Yang, A., McKeon, F. & Green, H. Association of p63 with proliferative potential in normal and neoplastic human keratinocytes . J. Invest. Dermatol. 113, 1099? 1105 (1999).

  46. 46

    Liefer, K. M. et al. Downregulation of p63 is required for epidermal UV-B-induced apoptosis. Cancer Res. 60, 4016? 4020 (2000).An interesting paper showing that the high levels of ΔN-p63 in immature keratinocytes must be eradicated for p53 to function.

  47. 47

    Heselmeyer, K. et al. Gain of chromosome 3q defines the transition from severe dysplasia to invasive carcinoma of the uterine cervix. Proc. Natl Acad. Sci. USA 93, 479?484 ( 1996).

  48. 48

    Johnson, R. L. & Tabin, C. J. Molecular models for vertebrate limb development. Cell 90, 979?990 (1997).

  49. 49

    Barrandon, Y. & Green, H. Three clonal types of keratinocyte with different capacities for multiplication. Proc. Natl Acad. Sci. USA 84, 2302?2306 ( 1987).

  50. 50

    Watt, F. M. Epidermal stem cells: markers, patterning and the control of stem cell fate . Phil. Trans. R. Soc. Lond. B 353, 831? 837 (1998).

  51. 51

    Lu. B., Jan, L. Y. & Jan, Y. N. Asymmetric cell division: lessons from flies and worms . Curr. Opin. Genet. Dev. 8, 392? 399 (1998).

  52. 52

    Buck, L. B. The molecular architecture of odor and pheromone sensing in mammals. Cell 100, 611?618 ( 2000).

  53. 53

    Frotscher, M. Cajal?Retzius cells, Reelin, and the formation of layers. Curr. Opin. Neurobiol. 8, 570?575 (1998).

  54. 54

    Eriksson, P. S. et al. Neurogenesis in the adult human hippocampus. Nature Med. 4, 1313?1317 ( 1998).

  55. 55

    Ollmann, M. et al. Drosophila p53 is a structural and functional homologue of the tumour suppressor p53. Cell 101, 91?101 (2000).References 55 57 describe the discovery of a single p53 homologue in flies with functional ties to the DNA damage response and apoptosis. They offer the promise of a genetic analysis of the prototypic p53 molecule.

  56. 56

    Brodsky, M. H. et al. Drosophila p53 binds a damage response element at the reaper locus. Cell 101, 103? 113 (2000).

  57. 57

    Jin, S. et al. Identification and characterization of a p53 homologue in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 97, 7301?7306 (2000).

  58. 58

    Ishioka, C. et al. Mutational analysis of the carboxy-terminal portion of p53 using both yeast and mammalian cell assays in vivo. Oncogene 10, 1485?1492 ( 1995).

Download references

Acknowledgements

We are grateful to V. Doetsch, D. Caput, C. Crum, H. van Bokhoven, P. Duijf, A. Sharpe, D. Roop, D. Kaplan and H. Green for enjoyable collaborations and continued support. F.M. is supported by grants from the National Institutes of Health and the American Cancer Society.

Author information

Related links

Related links

DATABASE LINKS

p53

p73

p63

Human chromosome 1p36

neuroblastoma

SAM domain

p21

GADD45

Bax

MDM2

cAbl

ubiquitin

p300

EEC syndrome

Dmp53

ENCYCLOPEDIA OF LIFE SCIENCES

Cerebral cortex development

Glossary

STERIC α-MOTIF

(SAM). Domain of 70 amino acids roughly conserved in many proteins and thought to participate in protein?protein interactions.

MDM2

Mouse double minute 2. Overexpressed in certain cancers and implicated in the ubiquitination and destabilization of p53.

p19ARF

A 19-kDa protein expressed from the INKA4A locus in response to oncogenic stimuli. It functions by stabilizing p53.

WILMS TUMOUR 1 PROTEIN

Zinc-finger transcription factor implicated in genitourinary development, and in tumorigenesis in these tissues.

LOSS OF HETEROZYGOSITY

Deletion or disruption of one of two copies of a gene.

KNUDSON'S TWO-HIT HYPOTHESIS

Loss of gene function through successive deletion or mutation of both alleles.

IMPRINTING

A genetic mechanism by which genes are selectively expressed from the maternal or paternal chromosomes.

DOMINANT-NEGATIVE

A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

MESENCHYME

Undifferentiated connective tissue present in the early embryo.

PYKNOTIC NUCLEI

Hypercondensed chromatin typical of cells undergoing apoptosis.

HYDROCEPHALUS

Condition marked by expansion of cerebral ventricles and compression of neural structures owing to block in flow or overproduction of cerebral spinal fluid.

CHOROID PLEXUS

Capillary bed containing the cerebral ventricles responsible for producing cerebral spinal fluid.

VOMERONASAL ORGAN

Cluster of sensory neurons in the nasal arch that detects pheromones and transmits this information to higher cortical centres.

MARGINAL ZONE

Superficial region of the cerebral cortex generally devoid of cells.

PIONEER NEURONS

One of several sets of early migrating neurons, which act as developmental and positional cues for local neurogenesis.

DENTATE GYRUS

Subdomain of hippocampal formation comprising granule cell neurons.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yang, A., McKeon, F. p63 and p73: p53 mimics, menaces and more. Nat Rev Mol Cell Biol 1, 199–207 (2000) doi:10.1038/35043127

Download citation

Further reading