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Cell Growth & Differentiation Vol. 12, 337-349, July 2001
© 2001 American Association for Cancer Research


Review

p53 Family Update

p73 and p63 Develop Their Own Identities

Meredith S. Irwin and William G. Kaelin1

Dana Farber Cancer Institute, Harvard Medical School [M. S. I., W. G. K.], and Howard Hughes Medical Institute [W. G. K.], Boston, Massachusetts 02115


    Introduction
 TOP
 Introduction
 Gene and Protein Structure
 Upstream Regulation of p73...
 Downstream Target Genes and...
 Role of p63 and...
 Conclusions and Outstanding...
 References
 
p53 continues to be one of the most intensively studied genes in cancer biology. p53 was initially identified >20 years ago as a binding partner for the SV40 T oncoprotein. Further studies revealed that p53 is a tumor suppressor gene that is mutated or inactivated in >50% of human cancers. Furthermore, germ-line p53 mutations cause hereditary cancer in both mice and humans. Molecular and biochemical assays revealed that the p53 protein is a sequence-specific DNA-binding transcription factor. p53 plays a central role in cellular responses to aberrant growth signals and certain cytotoxic stresses, such as DNA damage, by enhancing the transcription of genes that regulate a variety of cellular processes including cell cycle progression, apoptosis, genetic stability, and angiogenesis (1) . Interpreting the enormous quantity of p53 data, corresponding to almost 20,000 publications on the National Library of Medicine website, has become more complicated by the recent identification of two p53 paralogues, p63 and p73.

Until recently, p53 was thought to be a unique gene with no genetic paralogues. Daniel Caput identified the first p53-related gene, p73, ~4 years ago (2) . Several groups then independently identified the third member of the family, p63 (also known as p51, KET, p40, p73L, p53CP, and NBP; Refs. 3, 4, 5, 6, 7, 8, 9 ). Additional "p53-like" genes are unlikely to be identified because searches of the recently published human genome sequence revealed no additional p53 family members (10 , 11) . The structures of the p63 and p73 genes are more similar to one another than to p53. However, p63 and p73 can perform certain "p53-like activities." Similar to p53, both p63 and p73 can form homo-oligomers, bind DNA, activate transcription from p53-responsive genes, and induce apoptosis (3 , 5 , 12) . However, in contrast to p53, p63 and p73 give rise to multiple functionally distinct protein isoforms, some of which lack the NH2-terminal transactivation domain and can function as "dominant negative" proteins, which block the function of the corresponding full-length proteins. In addition, p63 and p73 are only rarely mutated in the large number of tumors examined to date and are thus unlikely to be classical tumor suppressor genes. However, altered expression of the various isoforms and heterotypic interactions among the different family members may still play a role in tumorigenesis. Also in contrast to p53, severe developmental abnormalities are observed in mice lacking either p63 or p73 and in humans with germ-line p63 mutations. This suggests possible tissue-specific functions for p63 and p73 during development. This article will review the growing compilation of reports addressing similarities and differences between p53, p63, and p73.


    Gene and Protein Structure
 TOP
 Introduction
 Gene and Protein Structure
 Upstream Regulation of p73...
 Downstream Target Genes and...
 Role of p63 and...
 Conclusions and Outstanding...
 References
 
The three major functional domains of p53 are an NH2-terminal transactivation domain, a central core DNA binding domain, and a COOH-terminal oligomerization domain. The more recently identified family members, p63 and p73, share significant homology with p53 in these three functional domains (13) . In striking contrast to p53, both p63 and p73 give rise to multiple functionally distinct protein isoforms attributable to alternative promoter utilization and alternative mRNA splicing. In this section, the similarities and differences of the genomic structures and protein domains of the three p53 family members are presented.

Genomic Organization and Alternative mRNA Isoforms.
Although the overall genomic organization of all of the p53 family members is similar, there are some significant differences (Fig. 1)Citation . Similarities among p53, p63, and p73 include exon/intron organization, inclusion of a large first intron, and a noncoding first exon (13) . The sizes of p73 and p63 are somewhat larger than p53. p53 is 20 kb and contains 11 exons. p73 and p63 are both >60 kb and contain 14 and 15 exons, respectively (13) . In addition to the full-length p53 (normal splice variant), an additional COOH-terminal splice form, alternative splice, has been described in murine cells and certain human tumor cells (14 , 15) . In contrast to p53, both p73 and p63 produce multiple mRNA transcripts as a result of alternative splicing. At least six different p73 isoforms have been identified affecting the p73 COOH terminus ({alpha}, ß, {gamma}, {delta}, {epsilon}, {zeta}; Refs. 2 , 16, 17, 18, 19 ). In addition to these COOH-terminal splice forms, two additional forms, {Delta}Np73{alpha} and {Delta}Np73ß, result from the use of an alternative promoter located in intron 3 (3) . Their protein products lack the NH2-terminal transactivation domain and, according to Yang et al. (20) , these {Delta}Np73 forms are the major p73 isoforms expressed in developing mice (20) . Another splicing variant, {Delta}exon2 p73, has been identified in certain breast cancer and neuroblastoma cell lines (2 , 21) . The structures of these different isoforms are shown in Figs. 1Citation and 2Citation .



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Fig. 1. Gene structure of p53 family members. Two p53 splice variants, NS p53 (normal splice) and AS p53 (alternative splice), are shown. Alternative splicing of p73 and p63 gives rise to the p73 isoforms {alpha}, ß, {gamma}, {delta}, {zeta}, and {epsilon} and p63 isoforms {alpha}, ß, and {gamma}. Additional isoforms, {Delta}Np73 ({alpha} and ß) and {Delta}Np63 ({alpha}, ß, and {gamma}), are transcribed from a cryptic promoter located within intron 3 (designated 3'). Arrows, transcriptional start sites. Exon sizes are drawn approximately to scale. Untranslated sequences are in black.

 


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Fig. 2. Functional domains of p53 family proteins. The transactivation (TA), DNA binding (DBD), oligomerization (OD), SAM, and proline-rich (PR) domains are shown for each of the family members. Alternative splice p53 undergoes splicing, which results in a replacement of p53 amino acids 364–390 with 17 unique amino acids. Alternative splicing of p73 and p63 mRNA (depicted in Fig. 1Citation ) leads to different COOH termini. These forms are identical through the end of the OD region. Unique coding sequences are represented as different diagonal and vertical striped patterns. The {Delta}Np73 and {Delta}Np63 forms lack the TA domain and contain unique NH2-terminal amino acids (represented by the shaded {Delta}N box) not found in the TA-containing forms. The asterisk located on p63 refers to a caspase recognition sequence, YVED. The entire SAM domain is present only in the {alpha} forms of p73 and p63.

 
The p63 gene also encodes at least six different proteins that share a common open reading frame (3) . These multiple isoforms are also the result of alternative splicing and the use of an alternative promoter. TA-p63{alpha}, TA-p63ß, and TA-p63{gamma} are transcribed from a 5' promoter, and {Delta}N-p63{alpha}, {Delta}N-p63ß, and {Delta}N-p63{gamma} are transcribed from a 3' promoter located in intron 3. As was true for p73, {Delta}N forms lack the NH2-terminal transactivation domain, whereas the TA forms include this transactivation domain (Ref. 3 ; see Figs. 1Citation and 2Citation ). In addition to these six forms, three additional TA forms, designated TA*p63{alpha}, TA*p63ß, and TA*p63{gamma} have been identified by Yang et al. (3) . The TA* refers to an additional 39-amino acid NH2-terminal extension encoded by the TA-p63 transcripts. TA* forms have not been described for p73 or p53. Various p63 and p73 isoforms differ significantly in both expression pattern and function. Some of these differences are discussed below and summarized in Table 1Citation .


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Table 1 Comparison of p53, p63, and p73 function and regulation

 
Protein Subdomains and COOH-Terminal Tails.
The conservation of the three major p53 subdomains among the family members is represented in Fig. 2Citation . The NH2-terminal transactivation domain is the least conserved of the three p53 subdomains (30% identical between p73 and p53 and 22% between p63 and p53; Ref. 22 ). As was true for p53, the acidic transactivation domain of p73 interacts with both the coactivator p300 and the oncoprotein MDM2 (discussed in more detail below). As alluded to above, the NH2-terminal transactivation domain is missing in the {Delta}Np73 and {Delta}Np63 isoforms. In contrast to p53, p73 contains a second potential activation domain within its COOH terminus (23) .

The central core DNA binding domain of p63 and p73 are 63 and 60% identical to p53, respectively (22) . In addition, the residues of p53 that directly contact DNA, including those most commonly altered by tumor-derived mutations, are conserved in the sequences of p63 and p73. Both p63 and p73 can bind to canonical p53 DNA-binding sites (24) . In studies described below, there is evidence that different family members differentially affect various "p53 responsive" promoters. Thus, there are likely to be differences among the p53 family members with respect to their optimal DNA-binding sequences.

The COOH-terminal oligomerization region (residues 326–355) of p53 is 38% identical with p73 residues 351–383 and 38% identical with p63 residues 355–404 (22) . p53 binds to DNA as a homotetramer. p53 family members preferentially form homo-oligomers rather than heteroligomers (25) . As for p53, the formation of p63 and p73 homo-oligomers is at least partially mediated through the conserved oligomerization domain. For a given p53 family member, the different isoforms described above bind to one another with varying affinities. The functional consequences of these interactions are discussed in later sections.

In addition to the well-characterized p53 domains described above, p53 also contains a proline-rich domain located within residues 60–90. Within this region are five PXXP motifs (P = proline and X = any amino acid; Ref. 26 ). Deletions and mutations within this domain affect both p53 proapoptotic activity and its ability to transcriptionally activate target genes, possibly through interactions with cellular proteins containing SH32 domains (26, 27, 28) . Both p63 and p73 contain several PXXP and PPXY (Y = tyrosine) motifs. The SH3 domain of the oncoprotein c-abl has been shown to bind p73 via a PXXP sequence located in the proline-rich region between the p73 DNA binding domain and the predicted oligomerization domain (29, 30, 31) . Functional consequences of c-abl binding to p73 are described below.

Similar to SH3 domains, WW domains (small 38–40 amino acid sequences characterized by two conserved tryptophan residues 20 amino acids apart) also bind proline-rich ligands (32) . Recently, Strano et al. (33) reported that the WW domain adaptor phosphoprotein YAP (yes-associated protein) also interacts with the PPPPY sequence of p73 and p63 (residues 482–488 and 498–504 respectively) but not p53. This interaction appears to increase p73 transactivation function.

The differential splicing of the p63 and p73 isoforms results in different COOH termini, all of which significantly extend the protein sequence beyond the region that is homologous to the 393 amino acid residues found in p53 (see Fig. 1Citation ). Additional important subdomains may exist within these COOH-terminal "tails." One subdomain that is unique to p63 and p73 is the SAM domain (34 , 35) . The SAM domain is a putative protein-protein interaction domain that has been found in multiple signaling proteins and transcription factors, many of which are important in developmental regulation. Only the {alpha} forms of p63 and p73 contain the SAM domain (p73{zeta} includes the majority of the SAM domain). Identification of the cellular proteins that bind to the p63 and p73 SAM domains and elucidation of their functions will likely significantly improve our knowledge of the functions of these newer family members. Further elaboration of the role of p63 in development is provided in later sections. Differences in the SAM and proline-rich domains of the different family members may reflect significant divergence in signaling and function.


    Upstream Regulation of p73 and p63
 TOP
 Introduction
 Gene and Protein Structure
 Upstream Regulation of p73...
 Downstream Target Genes and...
 Role of p63 and...
 Conclusions and Outstanding...
 References
 
The p53 protein is activated in response to a number of cellular stresses including DNA damage, oncogene activation, ribonucleotide depletion, mitotic spindle damage, and hypoxia (36) . Activation of p53 is generally a result of posttranslational modifications such as phosphorylation and acetylation, which affect protein stability and/or function. Once activated, p53 can induce a cell cycle growth arrest and/or apoptosis. Only a subset of the signals that regulate p53 affect p63 and p73. Recent data are helping to define unique regulatory pathways for each of the p53 family members. In this section, we will review the similarities and differences in the upstream regulation of p53, p63, and p73.

Growth and Differentiation Signals.
Recent data suggest that the tissue-specific expression of certain p63 and p73 isoforms may vary during changes in cell growth and differentiation. Hematopoietic and neuronal cell differentiation affect p73 levels. For example, p73 is up-regulated after T-cell stimulation. De Laurenzi et al. (18) reported that stimulation of both cultured and normal peripheral blood lymphocytes with phytohemagglutinin leads to an increase in p73 mRNA and an increase in apoptosis. Lissy et al. (37) also found that stimulation of the T-cell receptor with anti-CD3 antibody resulted in increases in both p73 protein levels and p73-dependent apoptosis. The state of myeloid cell differentiation has also been associated with changes in p73 levels. Tschan et al. (38) found that expression of p73 is markedly enhanced after differentiation of myeloid leukemic cells with all-trans retinoic acid.

p73 levels and function also vary with neuronal differentiation. Retinoic acid treatment of neuroblastoma cells led to increases in p73 protein levels and neuronal differentiation specific cell markers (39) . In addition, the high levels of {Delta}Np73ß in developing sympathetic neurons are dependent on the presence of high levels of NGF (40) . The role of {Delta}Np73 in NGF-regulated apoptosis is discussed below.

p63 levels appear to vary in keratinocytes and other squamous cells at different stages of growth and differentiation. TA-p63 levels increase whereas {Delta}Np63 levels decrease during keratinocyte differentiation (41, 42, 43, 44, 45) . p63 expression also varies in the cells that comprise the different compartments of stratified epithelium in such organs as skin and the cervix. The most immature basal layer progenitor cells have the highest levels of p63 when compared with the more differentiated cells in stratified epithelia (43 , 46 , 47) . These findings are discussed in more detail below as they pertain to the role of p63 in development and malignant transformation.

Ikawa et al. (48) reported a role for p63 in differentiation in two additional systems. First they detected an increase in the level of p51A (TA-p63{gamma}) and p51B (TA-p63{alpha}) during myeloblastic differentiation of C2C12 cells (48) . In addition, they suggested that p63 plays a role in erythroid differentiation. Overproduction of pTAp63{gamma} in an erythroleukemia cell line induced erythrodifferentiation, as demonstrated by increased hemoglobin production (49) . These reports supporting a role for p73 and p63 in differentiation, together with the data presented below, highlight potential differences among the p53 family members.

DNA Damage.
Initial studies suggested that p73, in contrast to p53, was not induced by DNA-damaging agents such as UV irradiation and actinomycin D (2) . The general notion that p73 was not up-regulated in response to DNA damage was challenged by several reports that showed that p73 is a target of the nonreceptor tyrosine kinase c-abl in response to certain forms of DNA damage. Gong et al. (30) showed that p73 is stabilized by cisplatin treatment and by coexpression with c-abl. As described above, p73 and c-abl form a complex via a p73 PXXP motif and the c-abl SH3 domain (29) . Furthermore, p73 is phosphorylated by c-abl on tyrosine residue 99 after {gamma}-irradiation of cells (29 , 31) . The proapoptotic activity of p73 is potentiated by c-abl and diminished in cells that lack c-abl. Because c-abl is itself phosphorylated and activated by the ataxia-telangiectasia-mutated (ATM) gene product, ATM may also be involved in the pathway leading to c-abl-dependent p73 activation (50) . These findings suggest that p73 participates in a mismatch-repair signaling pathway. Recent microarray gene expression profiles further support a role for p73 in response to and repair of DNA damage (51) . In addition to cisplatin, Taxol increases p73 accumulation, but UV irradiation, actinomycin D, and methylmethane sulfonate do not in the cell types examined to date (52) .

There are few studies addressing p63 response to DNA damage. TA-p63 levels increase and {Delta}Np63 levels decrease after UV-B irradiation (43 , 53) . In fact, this down-regulation of the "dominant negative" form of p63 is required for UV-induced apoptosis in skin (53) . This role for {Delta}Np63 in UV-induced apoptosis is discussed further below and in Fig. 2Citation . In summary, the induction of p63 and p73 by DNA damage may differ depending upon cell type and the nature of the DNA damage.

MDM2 and Ubiquitination.
Under conditions of normal cell growth, p53 is a short-lived protein, and its stability is very tightly regulated. p53 turnover is regulated by ubiquitination, a multistep process in which proteins are covalently modified by the addition of ubiquitin, which target proteins for degradation by the proteasome (54, 55, 56) . Polyubiquitination of p53 is carried out by the ubiquitin ligase MDM2. The polyubiquitination and degradation of p53 is influenced by a variety of factors including regulated changes in the subcellular localization of both it and MDM2. Moreover, MDM2 itself is a p53-inducible gene, and thus activation of p53 establishes a negative feedback loop wherein MDM2 limits p53 accumulation (57) .

Many cellular oncoproteins, including c-myc, E1A, Ras, and E2F1, induce the stabilization and accumulation of p53. This is attributable, at least in part, to the induction of a protein called ARF, which in turn binds directly to MDM2, both inhibiting the E3-ligase activity of MDM2 and interfering with the nucleocytoplasmic shuttling of MDM2 that is necessary for p53 degradation (58, 59, 60) . This p53 stabilization would be expected to result in cell cycle arrest or apoptosis, either of which would prevent tumor formation. Tumors commonly escape this mechanism by harboring mutations of p53 or another component of the "ARF-MDM2-p53" pathway (61) . Examples of the latter would include amplification of MDM-2 or homozygous deletion of ARF. ARF can also be silenced by hypermethylation.

In addition to its role in p53 degradation, MDM2 also binds to a sequence in the p53 NH2-terminal transactivation domain (amino acid residues 17–27) and thereby inhibits p53-dependent transactivation (62) . The MDM2 binding site in p53 is well conserved in both p63 and p73. Several groups have shown that MDM2 and the closely related MDMX bind to p73 and prevent it from binding to the transcriptional coactivators p300 and CBP (63, 64, 65, 66) . This leads to impaired p73-dependent transcriptional activation and diminished apoptosis. In addition, similar to p53, p73 can activate the MDM2 promoter (64 , 67 , 68) . In contrast to p53, however, MDM2 binding does not lead to p73 degradation. Indeed, MDM2 may actually stabilize p73{alpha} and p73ß (63 , 66) . One possible explanation for this resistance to degradation may relate to the differences between the p53 and p73 COOH termini. Although MDM2 binds to the p53 and p73 NH2 termini, mutations of the COOH terminus of p53 block MDM2-mediated degradation of p53 (69) . Thus, the COOH terminus of p53 plays an as yet poorly understood role with respect to MDM2-dependent proteolysis. Another possible explanation is provided by the recent finding by Wang et al. (70) that MDM2 and MDMX binding to p73 affects p73 subcellular localization, which might potentially affect p73 stability (70) .

Although MDM2 does not target p73 for polyubiquitination, it does appear that p73 stability is, at least indirectly, dependent upon the activity of the proteasome. Specifically, drugs that inhibit the proteosome increase p73 levels (63 , 66) . Thus, it is possible that p73 is polyubiquitinated in cells, although this remains to be proven. If so, it will be important to identify the relevant E3 ligase.

Finally, Minty et al. (71) detected SUMO-1 ("small ubiquitin like molecule") modification of p73{alpha}, which altered p73 subcellular localization and partially increased the rate of p73 degradation. SUMO also becomes conjugated to p53. Conjugation to SUMO affects p53 transcriptional activation function but does not appear to influence p53 stability (72 , 73) .

Recently, Wang et al. (70) showed that p63, unlike p73 and p53, does not bind to either MDM2 or MDMX, suggesting yet another difference between the family members. Although there are no data implicating ubiquitination pathways in p63 degradation, Ratovitski et al. (74) showed that p63 abundance is nonetheless subject to regulated proteolysis. They showed that p63 contains the YVED amino acid consensus sequence that is often recognized by caspase enzymes and that p63 protein levels were increased when such enzymes were inhibited pharmacologically.

Cellular Oncoproteins and Tumor Suppressors.
As described above, the ARF/MDM2 pathway affects the stability of p53 but not p73. Therefore, activation of this pathway by oncoproteins should not lead to induction of p73. Nonetheless, several groups have reported that oncoproteins do induce p73. This effect occurs at the level of p73 mRNA accumulation rather than at the level of p53 stabilization. For example, our group and others showed that the p73 promoter contains at least three E2F binding sites and that E2F1 can directly activate p73{alpha} and p73ß transcription (75, 76, 77, 78) . Further evidence that p73 is regulated by E2F1 includes the observation that p73 levels fall as cells are induced to exit the cell cycle after serum withdrawal and reaccumulates upon S-phase entry, a period in the cell cycle in which E2F-responsive genes are actively transcribed (76) .

Activation of p73 might provide one explanation for the earlier observation that E2F1 can induce apoptosis in the absence of functional p53 (76, 77, 78) . In keeping with this idea, Lissy et al. (37) showed that p73 mediates TCR-AICD (T-cell receptor activation-induced cell death) in lymphocytes. TCR-AICD was shown previously to be E2F1 dependent and p53 independent. This finding suggests a possible role for p73 in meditating the splenomegaly and lymphomas observed in E2F1-/- mice (79) .

Unlike p73, p63 levels are not affected by E2F1 in the cell lines examined to date. Zaika et al. (78) showed that other oncogenes, such as E1A and c-myc, also induce p73 levels. Whether the effect of E1A and c-myc on p73 relate to induction of E2F is not known.

The tumor suppressor gene product WT-1 has also been implicated in p53 and p73 regulation. WT-1 is heterozygously mutated or deleted in a variety of congenital anomaly syndromes and homozygously mutated in 15% of Wilm’s tumors. WT-1 is a transcription factor and can bind to p53, modulating its ability to activate target genes. Recently, Scharnost et al. (80) reported that the zinc finger motif of WT-1 binds to p73 and p63. Furthermore, they showed that WT-1 can inhibit p73-induced transcriptional activation of p53-responsive genes. However, in contrast to its stabilizing effect on p53, WT-1 does not stabilize p73{alpha}. This is again in keeping with the notion that the pathways that regulate the half-lives of p53 and p73 differ.

Viral Oncoproteins.
One of the first clear differences to emerge with respect to the p53 family members related to the fact that viral oncoproteins discriminate between them. Adenovirus E1B55, human papilloma virus E6 protein, and SV40 T antigen bind to, and inactivate, p53 during the course of viral transformation (81, 82, 83, 84) . These three proteins do not bind to p73 (24 , 85, 86, 87) . In fact, p73ß can induce growth inhibition and apoptosis in cancer cells that produce E6 (88) . Likewise, E6 and SV40 T antigen do not interact with p63 (89) . The adenoviral protein E4orf6 also binds to and antagonizes p53, but there have been conflicting reports as to whether it interacts with p73. Roth et al. (86) reported that E4orf6 does not affect p73 stability or the ability of p73 to activate transcription. Two other groups reported that E4orf6 binds to the COOH terminus of p73 and blocks transcriptional activation and colony suppression by p73 (87 , 90) . Thus, certain viral oncoproteins preferentially inactivate p53 while sparing p63 and p73, despite the high degree of similarity between these three proteins. This raises the interesting possibility that p73 and/or p63 facilitate, rather than inhibit, viral transformation.

Not all viral oncoproteins discriminate between the family members, however. The adenovirus E1A protein can block the interaction of the coactivators p300 and CBP with p73 and p53 (65 , 87 , 91 , 92) . Kaida et al. (93) reported that the human T-cell leukemia virus type 1 Tax oncoprotein could inactivate both p73 and p63, as well as p53, through their NH2-terminal transactivation domains.


    Downstream Target Genes and Function
 TOP
 Introduction
 Gene and Protein Structure
 Upstream Regulation of p73...
 Downstream Target Genes and...
 Role of p63 and...
 Conclusions and Outstanding...
 References
 
Little is known about which genes are regulated by p63 and p73 under physiological conditions. Current data suggest p63 and p73 can activate certain "p53-responsive promoters," leading to p53-like effects such as apoptosis. For example, p73 and p63 can activate the promoters of several p53-responsive genes implicated in cell cycle control, DNA repair, or apoptosis, including p21, Bax, MDM2, GADD45, 14-3-3{varsigma}, cyclin G, IGFBP3, and p53R2 (p53-inducible ribonucleotide reductase 2; Refs. 2 , 3 , 12 , 17 , 51 , 67 , 91 , 94, 95, 96 ). Most of these studies, however, relied on overproduction of p63 or p73 in cells. In theory, overproduction might mask subtle differences between the various p53 family members. Nonetheless, some differences are emerging. For example, p73 activates GADD45 more efficiently than p53, whereas p53 activates p21 more strongly than p73 (67 , 91 , 95) . De Laurenzi et al. (45) have shown that TA-p63, and to a much lessor degree p53 and p73, transactivate the promoters of loricin and involucrin, two genes whose expression is increased following differentiation of epidermal cells.

It will be especially important to determine whether there are genes that are under the control of specific p53 family members rather than by all 3. In this way, new insights into the nonredundant functions of the p53 family may be gleaned. The search for such target genes will likely be aided by the availability of genetically altered mice in which one or more p53 family members are inactivated as well as by advances in genomic technologies. For example, Zheng and Chen (97) identified AQP3 as a p73-responsive gene using cDNA subtraction assays. AQP3 is a member of a family of small transmembrane water and/or glycerol transporters. Its promoter has a "p53 response" element, and the AQP3 is strongly induced by p73ß and only weakly induced by p53 and p73{alpha}. Zheng and Chen (97) hypothesize that p73 regulation of AQP3 may mediate the putative activity of p73 in maintaining cerebral spinal fluid homeostasis because p73-/- mice have hydrocephalus attributable to defects in reabsorption of cerebrospinal fluid (see below).

Finally, the degree of transactivation for certain genes varies between different p73 and p63 COOH-terminal isoforms, suggesting that COOH-terminal sequences also affect function (67 , 98) . In many assays, for example, p73ß is a more potent transcriptional activator than p73{alpha} (17 , 91) . TA-p63{gamma}, but not TA-p63{alpha}, can transactivate the p21 promoter (3) . Likewise the p73 and p63 ß forms are more potent than the {alpha} forms as inducers of apoptosis. These results suggest that the {alpha} forms, which contain a unique 137 amino acids, may contain an "inhibitory" region not included in the ß and {gamma} forms. Conceivably, this inhibitory function is mediated by the SAM domain, which is unique to the {alpha} forms. This hypothesis is further supported by studies in which deletion of a region containing the SAM domain resulted in a mutant p73{alpha} protein with increased transcriptional activity comparable with p73ß (99) .

In addition to activating transcription, p53 can repress the activity of certain promoters, although the mechanisms underlying this activity are not clear (100) . Recently, Salimath et al. (101) showed that p73 can down-regulate endogenous VEGF gene expression by transcriptional repression of the VEGF promoter. Consistent with this observation, many lymphoid malignancies have transcriptionally silenced p73 and also show increased VEGF expression (102 , 103) . Whether the repression of the VEGF promoter by p73 is direct or indirect is not known. Nonetheless, these findings point to a possible role for p73 in the control of angiogenesis.

The {Delta}Np63 and {Delta}Np73 can affect gene expression by acting as dominant-negatives with respect to the corresponding full-length proteins. At least two, nonmutually exclusive, mechanisms can be evoked for the dominant-negative action of the {Delta}N forms. The first is that these proteins, which lack an NH2-terminal transactivation domain, bind to canonical p53 DNA-binding sites and prevent the binding of transcriptional activation-competent p53 family members. The second is that, while unbound to DNA, they oligomerize with, and hence sequester, transcriptional activation-competent p53 family members.

{Delta}Np63 and {Delta}Np73 have been implicated recently in certain apoptotic pathways (Refs. 40 , 53 ; Fig. 3Citation ). Pozniak et al. (40) reported that {Delta}Np73 is antiapoptotic in certain types of neurons. They showed that {Delta}Np73ß is the predominant p73 isoform in developing brain and sympathetic ganglia. The levels of {Delta}Np73ß are highest in sympathetic neurons maintained in NGF but decrease significantly upon NGF withdrawal. After NGF withdrawal these neurons undergo apoptosis. This neuronal cell death is mediated by two p53-dependent apoptotic pathways involving c-Jun NH2-terminal kinase kinase and the NGF receptor, respectively (104) . Because {Delta}Np73 can antagonize p53, the very low levels of {Delta}Np73 seen after NGF withdrawal may result in enhanced p53-dependent transcription and apoptosis. In keeping with this model, p73-/- neurons are more sensitive to apoptosis in response to either NGF withdrawal or p53 overexpression compared with wild-type neurons. Moreover, overproduction of {Delta}Np73 in these p73-/- cells prevents death (Fig. 3Citation ; Ref. 40 ).



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Fig. 3. Role for {Delta}Np73 in apoptosis. This diagram depicts a role for {Delta}Np73 in neuronal apoptosis. The level of {Delta}Np73, the predominant form of p73 in certain developing neurons, is highest when maintained in NGF (left side of diagram). After NGF withdrawal (- NGF), {Delta}Np73 levels decrease and cells undergo p53-dependent apoptosis. The possible mechanism(s) by which {Delta}Np73 may inhibit p53 activities include: (1) occupying of p53 DNA-binding sites (gray rectangles); and (2) hetero-oligomerization of {Delta}N forms with wild-type p53. A similar model has been proposed for {Delta}Np63 during UV-induced apoptosis in keratinocytes (discussed in text).

 
Liefer et al. (53) showed that {Delta}Np63 is antiapoptotic in UV-induced apoptosis. After UVB exposure, TA-p63 levels increase and {Delta}Np63 levels decrease. This down-regulation of the dominant-negative form of p63 is associated with increased UV-induced apoptosis. Furthermore, epidermal cells in transgenic mice expressing high levels of epidermal {Delta}Np63 are less sensitive to UV irradiation compared with cells from nontransgenic littermate controls. Similar to the proposed role of {Delta}Np73 in neuronal apoptosis, it is possible that the antiapoptotic properties of {Delta}Np63 are attributable to its ability to block p53-mediated transcriptional activation.

The dominant-negative forms of p63 may also play roles in keratinocyte differentiation. Prior to the identification of p63 and p73, Weinberg et al. (105) noted that the transcriptional activity of p53-responsive promoters paradoxically increases during keratinocyte differentiation, despite a decrease in p53 protein levels. Because TA-p63 levels increase and {Delta}Np63 levels decrease during differentiation (41, 42, 43, 44, 45) , it is possible that the increased transcriptional activity observed in this earlier study was either attributable to an increase in transcriptional activation by TA-p63 or a decrease in {Delta}Np63. Collectively, these studies suggest that down-regulation of {Delta}Np63{alpha} in response to UVB irradiation and during differentiation may be important in determining the fate of epidermal cells.


    Role of p63 and p73 in Cancer and Development
 TOP
 Introduction
 Gene and Protein Structure
 Upstream Regulation of p73...
 Downstream Target Genes and...
 Role of p63 and...
 Conclusions and Outstanding...
 References
 
The function of the p53 tumor suppressor protein is directly or indirectly compromised in most sporadic human tumors. In addition, patients with germ-line mutations in p53 develop the Li-Fraumeni hereditary cancer syndrome, characterized by an increased risk of developing a spectrum of tumors including breast cancers, sarcomas, and brain tumors (106) . In contrast to p53, p63 and p73 are only rarely mutated in human tumors. Furthermore, unlike p53-/- mice, p63-/- and p73-/- mice are not tumor prone but instead manifest multiple developmental abnormalities (20 , 107 , 108) . The data supporting roles for p63 and p73 in cancer, development, and human diseases are presented below.

Role of p73 in Malignancy: Expression Levels and Interactions with p53.
p73 is located at chromosome 1p36, a region that is frequently deleted in a variety of human tumors including neuroblastoma, melanoma, breast, and colon cancer (109) . The mouse p73 gene is also located in a region implicated in murine cancer. Specifically, mouse p73 maps to the distal part of chromosome 4, a region lost in {gamma}-radiation-induced murine T-cell lymphomas (110) . The chromosomal location of p73, together with its similarities to p53, initially led to speculation that p73 was a tumor suppressor gene. However, p73 does not conform to Knudson’s two-hit hypothesis because extensive studies have revealed only rare p73 mutations in both cell lines and primary tumors, including tumors with 1p36 deletions (109) . Interestingly, the few p73 mutations detected have been associated with potential functional consequences, including two COOH-terminal mutations in neuroblastoma that impair p73 transactivation function (23) . Loss of p73 expression may also contribute to the pathogenesis of a subset lymphomas and leukemias. Several reports documented transcriptional silencing of p73 because of hypermethylation in these disorders (111 , 112) . These data, together with the findings that p73 is involved in T-cell activation-induced cell death and may be involved in radiation-induced murine lymphomas, suggest a role for p73 in lymphoid proliferation and neoplasia.

Initial reports suggested that the failure to detect mutations in the remaining p73 allele in tumors with 1p36 deletions might relate to imprinting. Specifically, it was suggested that p73 was monoallelically expressed in tumors such as neuroblastoma (2 , 113) . If true, loss of the transcribed allele, such as through 1p36 deletion, would be sufficient to make a cell functionally null for p73. Subsequent studies, however, have challenged the idea that p73 is imprinted. In fact, although some studies documented monoallelic expression in certain tissues and tumors, a number of different studies have demonstrated biallelic expression of p73 (114, 115, 116, 117, 118, 119, 120, 121) . Furthermore, p73 mRNA and protein levels tend to be higher, and not lower, in tumor tissue compared with surrounding normal tissue. Ependymomas, breast, lung, prostate, ovarian, colorectal, esophageal, and bladder cancers have all been reported to have elevated p73 levels compared with their normal tissue counterparts (120, 121, 122, 123, 124, 125, 126, 127, 128, 129) . One explanation for this increased expression may be a "loss of imprinting," as has been reported for a subset of tumors. An alternative possibility relates to oncogenic activation of p73 by E2F1. E2F dysregulation is common in tumors, and thus, free E2F1 may transcriptionally activate p73. Why some tumor cells tolerate high levels of p73 whereas others undergo apoptosis is not clear. In addition, there have been no reports addressing the expression of the potentially antiapoptotic {Delta}Np73 forms in tumors.

Several groups showed that a subset of p53 mutants can bind to p73 and block p73-dependent transactivation and apoptosis (130, 131, 132, 133) . This interaction appears to be mediated by the core DNA-binding domains rather than oligomerization domains (132 , 133) . Moreover, this interaction is enhanced when p53 codon 72 encodes Arg rather than Pro by virtue of a common p53 polymorphism (Ref. 131 ; Fig. 4Citation ). This may explain why Arg-72 p53 mutants cooperate with Ras to transform cells and inhibit p73-dependent apoptosis more effectively than their Pro-72 counterparts. Moreover, the Arg allele is preferentially mutated and retained in squamous cancers of the skin and vulva arising in p53 Arg/Pro germ-line heterozygotes (131 , 134) . Overall, these data suggest that inactivation of p73 by certain p53 mutants may provide a selective advantage in promoting tumorigenesis. Interestingly, many of the same p53 mutants that bind p73 have also been associated with an increased resistance to certain chemotherapeutic agents (135 , 136) . It remains to be seen whether this chemoresistance is attributable to heterotypic interactions between mutant p53 and p73 (or possibly p63).



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Fig. 4. Role of mutant p53 binding to p73. Both p53 and p73 can induce apoptosis and growth arrest. Some of the stress signals that activate p53 and p73 are depicted in this figure. p53 mutation is common in human cancers. Certain p53 mutant proteins bind to p53 and inhibit p53-dependent transactivation and apoptosis. In addition, a subset of p53 mutant proteins can also bind to and inhibit p73-dependent activities. The interaction between mutant p53 and p73 is enhanced when the p53 codon 72 polymorphism encodes an Arg rather than a Pro (bold line).

 
In summary, there is no evidence that p73 is a classical tumor suppressor gene. It remains possible that inactivation of p73, such as resulting from hypermethylation or binding to mutant p53, contributes to tumorigenesis in some cases. The finding the p73 levels are increased in many tumors, together with the finding that viral oncoproteins discriminate between p53 and its cousins, leaves open the heretical notion that p73 may enhance, rather than suppress, transformation in certain tissues.

p63 in Malignancy: Possible Role as an Oncogene.
p63 maps to chromosome 3q27–29, a region that is altered in a variety of cancers including cancers originating in the lung, cervix, and ovary (109) . As was true for p73, p63 mutations are rare in both primary tumors and cell lines. The rare mutations identified to date map to the p63 DNA binding domain (109) . Despite the lack of frequent mutations, alterations in expression of specific p63 isoforms may contribute to tumorigenesis. As is the case for p73, p63 levels are often higher in malignant tissue compared with normal tissue. Hibi et al. (137) have proposed that {Delta}Np63 (also called p40AIS) functions as an oncogene. They, along with Hibi et al. (137) , Yamaguchi et al. (138) , and Crook et al. (139) , demonstrated high levels of expression of {Delta}Np63/p40AIS in squamous cell carcinomas of the aerodigestive tract. The authors of these studies hypothesize that {Delta}Np63 may function as an oncoprotein. As described above, this may occur via formation of inactive hetero-oligomers or possibly by competition with wild-type p53 for DNA binding sites. Immunohistochemical studies of biopsy specimens obtained from malignant and premalignant lesions of the cervix and endometrium reveal that the highest levels of p63 typically occur in the most undifferentiated cells (46 , 47 , 140) . In these pathological studies, it remains to be determined whether the high levels of p63 observed are causative or correlative.

Interestingly, the studies of Ratovitski et al. (74) described above showed that wild-type, but not mutant, p53 proteins enhance the caspase-dependent cleavage of {Delta}Np63. Thus, down-regulation of the "oncogenic" forms of p63 may contribute to tumor suppression by wild-type p53. As was true for p73, certain p53 mutants can bind to and inactivate p63 (131 , 133) . The net effect of such mutant p53-p63 interactions presumably would be influenced by the relative abundance of the TA and {Delta}N forms of p63 present.

p73 in Development: Role in Neuronal and Pheromonal Pathways.
Mouse models provided the first clues as to the potential role of p73 in development. In contrast to the ubiquitous expression of p53 mRNA, murine p73 mRNA is restricted to the epidermis, sinuses, inner ear, and brain (22) . p73-/- mice are viable, but unlike p53-/- mice, do not develop tumors (20 , 141) . Instead these mice, which are functionally deficient for all of the known p73 isoforms, demonstrate significant abnormalities including chronic infections, inflammation, hydrocephalus, hippocampal dysgenesis, and defects in pheromone-sensory pathways (20) . The infections observed do not appear to be attributable to quantitative or functional deficiencies in granulocytes or lymphocytes. Instead, these infections may be attributable to epithelial barrier dysfunction. The hydrocephalus appears to be attributable to overproduction of cerebrospinal fluid by the epithelial cells lining the choroid plexus. Abnormal social behavior in p73-/- males, such as lack of interest in females, decreased mating, and attenuated aggression responses, have been attributed to defects in the neuroepithelium of the vomeronasal organ. In wild-type mice the vomeronasal organ, an accessory olfactory structure involved in pheromone detection, expresses very high levels of p73. On the basis of these data, Yang et al. (20) hypothesize that p73 may have a central role in sensing certain environmental and homeostatic stimuli (20) .

The hippocampal dysgenesis observed in p73-/- mice involves disappearance of a specific zone of neurons (Cajal-Retzius cells) in the hippocampus and an enhancement of developmental sympathetic neuronal death (20 , 40) . During neuronal development, {Delta}Np73 may be the relevant functional isoform because it has been shown to perform "anti-apoptotic" functions in primary neurons (as reviewed in earlier sections and Fig. 3Citation ). These data, together with reports linking p73 to neuronal differentiation, support a role for p73 (perhaps predominantly {Delta}Np73) in neural development and apoptosis. Generation of various conditional and isoform-specific p73 knockout mice should more clearly define the specific roles of the different p73 isoforms in development.

p63 in Ectodermal Development and Disease.
Despite the structural and functional similarities between p73 and p63, the characteristics of mice lacking p63 are very different from those lacking p73. This is attributable to, at least partly, differences in patterns of tissue expression. Murine p63 is most highly expressed in proliferating basal cells of the epidermis, cervix, urothelium, and prostate (22) . Unlike p73-/- mice, which grow into adulthood, p63-/- mice die shortly after birth. The significant skin, limb, and craniofacial defects of p63-/- mice suggest a role for p63 in several aspects of ectodermal differentiation and development (107 , 108) . The limbs of these mice are absent or truncated as a result of failure of the apical ectodermal ridges to differentiate. There is an absence of all squamous epithelia and their derivatives including hair follicles, teeth, mammary, lacrimal, and salivary glands. Other sites of stratified squamous epithelia, including the tongue, esophagus, proximal stomach, urinary bladder and cervix, demonstrate abnormalities. Their skin does not progress beyond an early developmental stage, lacks normal stratification, and fails to express certain differentiation markers such as keratin. The defects are not solely attributable to abnormal differentiation because the rare embryonic remnant skin cells detectable in such mice stain positively for other markers of terminal differentiation, such as loricin, and show characteristics indicative of apoptosis. Thus, Yang et al. (107) conclude that loss of p63 results in a decrease in the regenerating population of basal epithelial cells rather than a defect in the upward differentiation of stratified epithelia, implicating p63 in the process of epithelial stem cell renewal.

Further clues regarding the role of p63 in development came from the identification of germ-line p63 mutations in human patients with a spectrum of EEC syndromes (142, 143, 144, 145) . Certain craniofacial and limb defects of these patients resemble those described in p63-/- mice. Celli et al. (142) identified heterozyous p63 mutations in nine unrelated families with EEC and the EEC-like disorder, LMS. EEC/LMS is a rare autosomal dominant disorder in which there is highly variable expression and penetrance. Ectodermal dysplasia is manifested by changes in skin, hair, nails, teeth, lacrimal duct, and urogenital tract and can be associated with conductive hearing loss, facial dysmorphism, chronic and recurrent respiratory infections, and developmental delay. Most of the mutations (eight of nine) identified would be predicted to affect p63 DNA binding ability; a ninth mutation results in a frameshift of the p63{alpha} but not ß or {gamma} subtypes. Celli et al. (142) hypothesize that EEC does not result from haploinsufficiency because mice heterozygous for p63 have no craniofacial or limb defects. Instead, EEC patient-derived {Delta}Np63 proteins may exert a dominant effect. Some of the patient-derived {Delta}Np63{alpha} proteins, unlike wild-type {Delta}Np63{alpha}, are unable to bind DNA and are unable to inhibit the transcriptional activity of p53 and certain TA-p63 isotypes. The nature and biochemical basis of the putative "gain of function" of the eight p63 DNA-binding domain mutations observed in EEC are unknown. Interestingly, the ninth mutation encodes a truncated TA-p63{alpha} protein that gains the ability to transcriptionally activate a p53-responsive promoter, which is not activated by the wild-type TA-p63{alpha}. Recently, two additional DNA-binding domain p63 mutations were identified in another limb malformation syndrome, SFHM (143) . Furthermore, McGrath et al. (145) identified p63 mutations in eight families with the related Hay-Wells syndrome, which is also known as AEC syndrome (145) . Interestingly, these p63 mutations mapped to the SAM domain of p63{alpha}. As mentioned previously, the SAM domains are protein-protein interaction domains, which are often involved in developmental processes. Thus, it is possible that mutations in p63{alpha} SAM may affect important protein interactions and/or signaling pathways involved in limb and craniofacial development. Although some of the characteristics of AEC overlap with those of EEC, LMS, and SFHM, the phenotypic findings of severe scalp dermatitis and fused eyelids are distinguishing features of AEC. Clinical variability is one of the hallmarks of the EEC syndromes, and thus the findings of p63{alpha} mutations in the SAM domain in AEC, in contrast to p63{alpha} mutations in the DNA-binding domain in EEC and SFHM, suggest a genotype-phenotype correlation. These data, together with the striking phenotype of the p63 knockout mice, implicate p63{alpha} (and {Delta}Np63{alpha}) in ectodermal development. Further understanding of this role of p63 in normal epithelial cell stratification and development may shed light on its role in epithelial cancers.


    Conclusions and Outstanding Questions
 TOP
 Introduction
 Gene and Protein Structure
 Upstream Regulation of p73...
 Downstream Target Genes and...
 Role of p63 and...
 Conclusions and Outstanding...
 References
 
Over the past 5 years, studies of the newly identified p53 family members, p63 and p73, have revealed several structural and functional similarities. The p53 transactivation, DNA binding, and oligomerization domains are highly conserved among all family members. Like p53, p63 and p73 can form oligomers, bind DNA, and transactivate the promoters of known p53-inducible genes and induce apoptosis. In addition, certain cellular and viral proteins known to bind and regulate p53 activity likewise can bind to p63 and p73.

Despite the fact that p63 and p73 can mimic many p53 activities in vitro, more recent studies highlight significant differences between the family members. In contrast to p53, p63 and p73 give rise to multiple functionally distinct protein isoforms attributable to alternative promoter utilization and alternative mRNA splicing. The {Delta}N forms, which lack the NH2-terminal transactivation domain, can function as "dominant-negative" proteins, blocking certain activities of the corresponding full-length proteins. Differences in abilities of various isoforms to transactivate target genes and induce apoptosis may be attributable to coding differences in their respective COOH termini. In addition, the {alpha} forms contain a unique SAM domain, which may be important for as-yet-undefined protein-protein interactions. Differences in the upstream signaling pathways involved in activation of each of the family members are also becoming apparent. Only a subset of the DNA-damaging agents that induce p53 also induce p73. Many cellular and viral oncoproteins also discriminate between p53 and the newer family members. Finally, it is becoming apparent that p63 and p73 are not classical tumor suppressor genes. In particular, these genes are not frequently mutated in tumors, and germ-line mutations in these genes do not cause tumors in mice. Instead, mice with deletions in p63 and p73 have significant developmental abnormalities.

Thus, the most recently identified members of the p53 family, p63 and p73, have overlapping as well as distinct biological functions. Despite the significant recent advances in understanding the unique roles of each of the family members, there are still several outstanding questions. What are the patterns of expression of the different p63 and p73 isoforms during both normal development and tumorigenesis? Studies of the relative expression of different isoforms in tumors might be aided by the use of isoform-specific antibodies. Studies of knockout mice in which specific isoforms, such as {Delta}Np73 and {Delta}Np63, are deleted should also provide insight into the unique functions of each isoform. Another important question relates to defining the roles the three different p53 family members play during differentiation and apoptosis in various physiological settings. For example, there are already data implicating p63 in epithelial cell stem cell renewal and differentiation and data implicating p73 in neuronal apoptosis. Finally, homotypic and heterotypic interactions among the three family members may play roles in tumorigenesis. Understanding the complexity of these interactions may facilitate the development of anticancer therapeutics that seek to induce the activation of "p53-responsive" genes in cells lacking wild-type p53.


    Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Howard Hughes Medical Institute, Dana Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Mayer Building, Room 457, Boston, MA 02115. Phone: (617) 632-3975; Fax: (617) 632-4760; E-mail: william_kaelin{at}dfci.harvard.edu Back

2 The abbreviations used are: SH3, src homology 3; SAM, sterile {alpha} motif; NGF, nerve growth factor; MDM2, murine double minute 2; ARF, alternate reading frame; WT-1, Wilm’s tumor-1; AQP3, aquaporin 3; VEGF, vascular endothelial growth factor; NGF, nerve growth factor; EEC, ectrodactyly, ectodermal dysplasia, and cleft lip, with or without cleft palate; LMS, limb mammary syndrome; SFHM, split-hand/split-foot malformation; AEC, ankyloblepharon-ectodermal dysplasia-clefting. Back

Received for publication 4/27/01. Accepted for publication 5/ 8/01.


    References
 TOP
 Introduction
 Gene and Protein Structure
 Upstream Regulation of p73...
 Downstream Target Genes and...
 Role of p63 and...
 Conclusions and Outstanding...
 References
 

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