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.
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?
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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.
- STERIC α-MOTIF
(SAM). Domain of ∼70 amino acids roughly conserved in many proteins and thought to participate in protein?protein interactions.
Mouse double minute 2. Overexpressed in certain cancers and implicated in the ubiquitination and destabilization of p53.
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.
A genetic mechanism by which genes are selectively expressed from the maternal or paternal chromosomes.
A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.
Undifferentiated connective tissue present in the early embryo.
- PYKNOTIC NUCLEI
Hypercondensed chromatin typical of cells undergoing apoptosis.
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.
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