REVIEW

The Emerging p53 Gene Family

William G. Kaelin, Jr.

Affiliations of author: Howard Hughes Medical Institute and Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.

Correspondence to: William G. Kaelin, Jr., M.D., Dana-Farber Cancer Institute, Mayer Bldg., Rm. 457, 44 Binney St., Boston, MA 02115 (e-mail: william_kaelin{at}dfci.harvard.edu).


    ABSTRACT
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
Perturbation of p53 protein function is a common, if not universal, finding in human cancer. Tumor suppression by p53 is due, at least in part, to its ability to activate transcription of certain genes involved in cell cycle control and apoptosis (programmed cell death). Two additional members of the mammalian p53 family, p73 and p51, which is also known as p40, p63, KET, or p73L, were recently identified. Both of these proteins share substantial sequence homology with p53 and can, at least when overproduced, activate p53-responsive promoters and induce apoptosis. Nonetheless, data on differences between these proteins and p53 are emerging. For example, p73 is not induced by DNA damage and is not targeted for inactivation by viral oncoproteins such as simian virus 40 (SV40) T antigen, adenovirus E1B 55K, and human papillomavirus E6. In contrast to p53, neither p73 nor p51 appears to be frequently mutated in human cancers on the basis of the limited studies reported to date. Finally, unlike p53, cells produce multiple p73 and p51 isoforms as a result of alternative splicing, and production of p73 and p51 appears to be restricted to certain tissues. Additional studies are required to determine the role, if any, that p73 and p51 play in cell growth control and carcinogenesis.



    INTRODUCTION
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
Computer databases of cloned DNA sequences are growing exponentially. Perusal of these databases suggests that many genes are, in fact, members of gene families. For example, there are currently three cloned members of the retinoblastoma gene family (RB-1, p107, and p130) and four cloned p16INK4A-like cyclin-dependent kinase (cdk) inhibitors (p15INK4B, p16INK4A, p18INK4C, and p19INK4D). (In this review, the following nomenclature convention is used: Gene names are italicized, whereas protein names are not.) The p53 tumor suppressor gene, until recently, provided an exception to this rule. This observation was all the more striking given the central role of p53 in cell growth control and carcinogenesis. Several laboratories (1-6), however, have now identified two additional members of the p53 family (Table 1).Go This review will focus on the identification and preliminary characterization of these family members.


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Table 1. Mammalian p53 gene family members

 

    ROLE OF P53 IN HUMAN CANCER
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
Approximately 50% of all human cancers lack a wild-type p53 allele and thus fail to produce a normal version of the p53 protein (7-10). Furthermore, p53 function is altered in many tumors that retain a wild-type p53 allele. For example, the development of cervical and anogenital cancers has been linked to degradation of p53 by the human papillomavirus E6 protein (11-17). Similarly, p53 is both neutralized and degraded by the MDM2 (mouse double minute 2) oncoprotein (HDM2 in humans) (18-21). Sarcomas often lack wild-type p53 or overproduce HDM2 (22,23). Recent studies (24-28) suggest that the p14ARF (ARF = alternative reading frame) protein (also known as p19ARF in mice) is critical for p53 to respond to certain oncogenic stimuli, perhaps by modulating the interaction of HDM2 with p53. p14ARF is encoded by the same genetic locus that encodes the p16INK4A cdk inhibitor (29,30). This locus is mutated, deleted, or hypermethylated in a wide variety of cancers. Finally, p53 mutations are rare in neuroblastomas, but the p53 protein in these tumors is seemingly sequestered in the cytoplasm (31,32). In summary, neutralization of p53 function is a common, and possibly requisite, step in human cancer. The importance of p53 is further underscored by the observation that a number of unrelated DNA tumor viruses, including polyomaviruses, adenoviruses, and papillomaviruses, encode oncoproteins that inactivate p53 function (11-17,33-43). Furthermore, germ line p53 mutations give rise to tumors in both mice and humans (44-46).

The majority of tumor-derived p53 mutations encode stable p53 missense mutants (7-10,47). Furthermore, the intracellular concentrations of these mutants typically exceed those observed for wild-type p53. This situation is in stark contrast to other tumor suppressor genes where frameshift mutations and gross deletions are common and where missense mutants are often unstable. This led earlier to the notion that certain p53 mutants might acquire new properties (gain-of-function) that might contribute to their ability to promote transformation. In keeping with this view, some p53 mutants can inactivate wild-type p53 through heteroligomerization. Furthermore, some p53 mutants can enhance transformation when introduced into p53 nullizygous cells (48-52). This observation suggests that properties other than heteroligomerization with p53 must contribute to their ability to promote transformation.


    P53 FUNCTION
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
p53 is normally a short-lived protein. Destruction of p53 is likely mediated, at least in part, by binding to complexes containing HDM2 and p300 (18,19,53). The importance of the p53-HDM2 interaction is underscored by the finding that MDM2 nullizgous embryos are not viable unless p53 is likewise deleted (54). In response to certain stimuli, such as DNA damage or oncogene-induced proliferation, p53 becomes stabilized (27,28,55). In response to DNA damage, the N-terminus of p53 becomes phosphorylated (56,57). Members of the ATM (ataxia-telangiectasia mutated)/ATR (ataxia-telangiectasia and Rad3 related) family and DNA-PK (DNA-dependent protein kinase) have been implicated in this process (56-58). Phosphorylation of p53 may affect its interaction with HDM2 as well as its ability to bind to DNA (56-58). Similarly, certain oncogenes induce the production of p14ARF (27,28,59,60). p14ARF can physically interact, at least in vitro, with both HDM2 and p53 (24-26). p14ARF antagonizes the effects of HDM2 on p53, although the precise biochemical mechanism underlying this activity is not known.

Stabilization of p53 can induce either a cell cycle arrest or programmed cell death (apoptosis). These activities are due, at least in part, to the ability of p53 to form homotetramers that bind to specific DNA sequences and activate transcription. The ability of p53 to form productive homotetramers is influenced by residues within its C-terminus. The importance of p53 DNA-binding activity is underscored by the p53 crystal structure which reveals that many of the p53 residues that directly contact DNA are mutational hotspots in human cancer (61,62). A number of p53 target genes have been identified. Examples of cell cycle-control genes include p21 (also known as WAF1 [wild-type p53-activated fragment 1], CIP1 [cdk-interacting protein 1], or SDI1 [senescent cell-derived inhibitor 1]) and 14-3-3 sigma (63,64). The former inhibits cyclin-dependent kinases and induces a G1/S block, and the latter inhibits Cdc25c and induces a block at the G2/M phase of the cell cycle (63,65-68). Examples of apoptotic genes induced by p53 include BAX (Bcl-2-associated protein X) and a family of genes implicated in changes in the cellular redox state (69,70).


    CLONING OF P73
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
During a search for novel interleukins, Caput and co-workers (1) serendipitously identified a complementary DNA that was predicated to encode a p53-like protein. The corresponding gene, called p73, maps to chromosome 1p36, a region that is frequently deleted in a variety of human cancers. The genomic organizations of p53 and p73 are highly similar, suggesting that they are ancestrally related (1). Importantly, the region of highest similarity between p53 and p73 corresponds to the p53 core DNA-binding domain. Indeed, all of the p53 DNA contact residues are conserved between p53 and p73. In addition, p73 and p53 share substantial similarity in regions corresponding to the N-terminal transactivation and C-terminal transactivation domains of p53. Caput and co-workers (1) noted that cells contained at least two alternatively spliced p73 messenger RNAs (mRNAs), which they designated alpha and beta. The beta isoform lacks exon 13, resulting in a frameshift and truncation of the protein C-terminal to the putative oligomerization domain.


    EXPRESSION OF P73
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
In northern blot assays, Senoo et al. (5) detected p73 transcripts in human thymus, prostate, heart, liver, skeletal muscle, and pancreas. The presence of p73{alpha} and p73ß protein in mammalian cell extracts has been confirmed by immunoblot analysis using anti-p73 monoclonal antibodies that are specific to this p53 family member (71).


    FUNCTIONS OF P73
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
Both p73{alpha} and p73ß can, as predicted, bind to canonical p53 DNA-binding sites in electrophoretic mobility shift assays in vitro (71). Whether these proteins bind to DNA as homoligomers or heteroligomers is currently unknown. In this regard, Caput and co-workers (1) noted that p73ß bound to itself and weakly to p73{alpha} in yeast two-hybrid assays. Furthermore, Marin et al. (71) found that p73{alpha}, whether translated in vitro or isolated from mammalian cell extracts, coimmunoprecipitated with p73ß.

Both p73{alpha} and p73ß can, at least when overproduced, activate transcription from p53-responsive promoters and induce apoptosis in cells irrespective of their p53 status (1,72). This activity requires an intact p73 DNA-binding domain. The upstream signals that act on p73 are unknown. In this regard p73, unlike p53, is not induced by DNA-damaging agents such as dactinomycin and UV irradiation (1).


    ALTERATIONS OF P73 IN HUMAN CANCER
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
The apparent similarity of p73 to p53, together with the fact that p73 maps to a region of the genome that is frequently deleted in human cancers, led to the hypothesis that it is a tumor suppressor gene. The Knudson two-hit model would predict that the retained p73 allele in tumors that have sustained chromosome 1p deletions should harbor an inactivating mutation. Thus far, however, no such mutations have been identified (1,73-76). One potential explanation for this finding, first offered by Kaghad et al. (1), is that the p73 locus is monoallelically expressed. If this explanation is true, loss of the transcribed allele would be sufficient to deprive the cell of p73 and promote carcinogenesis. A precedent for this scenario is provided by the p57KIP2 cdk inhibitor. p57KIP2 is imprinted, and loss of the transcribed allele has been implicated in the development of the Beckwith-Wiedemann syndrome (77). Alternatively, perhaps haploinsufficiency of p73 is sufficient to provide a growth advantage to tumor cells in vivo.

The above considerations would then suggest that p73 mutations might be enriched in tumors that had not undegone 1p deletions. To date, however, no such mutations have been identified (1,74-76,78). Second, the notion that monoallelic expression of p73 contributes to carcinogenesis is currently being challenged. Nomoto et al. (74) found evidence of biallelic p73 expression, although this expression varied between different tissues and different individuals. Mai et al. (78) documented biallelic expression of p73 in five assessable lung cancers, whereas one allele was expressed in the surrounding normal tissue. Kovalev et al. (76) confirmed biallelic expression of p73 in five of six neuroblastomas and in three of three assessable normal individuals Finally, and most importantly, several groups (74-76,78) have found that p73 mRNA levels are increased, rather than decreased, in tumor tissue relative to surrounding normal tissue.

Still, it remains possible that monoallelic expression of p73 contributes to cancer in a subset of human tissues. Furthermore, it is possible that the degree to which p73 is monoallelically expressed is itself a polymorphic trait in the human population. The results of Nomoto et al. cited above are at least consistent with this view. Finally, p73 produces multiple mRNA transcripts (1,79). For the highly related p51 gene (see below), multiple transcripts arise as a result of alternative splicing and the use of different promoters (4,6). It is theoretically possible that some p73 transcripts will be biallelically expressed and others will not be. For this reason, it will be important to compare the methods used by different investigators who attempt to address this issue. Those issues surrounding monoallelic and biallelic expression of p73 will need to be resolved before determining whether or not p73 is a tumor suppressor gene.


    DISCRIMINATION BETWEEN P73 AND P53 BY VIRAL ONCOPROTEINS
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
Viral oncoproteins have been invaluable reagents for the study of tumor suppressor proteins such as p53 and pRB. Indeed, p53 was first identified as a T-antigen-binding protein (80,81). T antigen binds to the DNA-binding region of p53 and hence the region that is most highly conserved between p53 and p73 (36,37). Despite this fact, T antigen does not bind to p73 (71). The adenoviral E1B 55K protein interacts with the p53 transactivation domain, and the residues critical for this interaction are highly conserved between p53 and p73 (33,39-41). As was true for T antigen, however, the E1B 55K protein does not bind to p73 (71,82). Furthermore, p73 protein levels are readily detected in cells that have been transformed by simian virus 40 (SV40) T antigen or a fragment of the adenoviral genome containing E1A and E1B (71). Finally, E6 interacts with residues in both the p53 core domain and in its C-terminus (14,16,42,43). E6 does not bind to p73 and does not target p73 for degradation (71). Indeed p73, but not p53, can induce apoptosis in E6-transformed cells (83).

Given the high degree of similarity between p53 and p73, it is surprising that none of the viral oncoproteins described above interact with p73. Specifically, one or more of these oncoproteins might have been expected to bind to p73 even if by chance alone (i.e., irrespective of whether p73 is a tumor suppressor protein). The fact that all three of these proteins discriminate between p53 and p73 suggests that sparing one or more of p73's functions is advantageous for DNA tumor viruses. For example, p73 might facilitate viral replication. Indeed, these results raise the seemingly heretical possibility that p73, when present at physiologic concentrations, promotes rather than inhibits cell proliferation.


    IS P73 A TUMOR SUPPRESSOR GENE?
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
As described above, there are no firm genetic data at present to support the notion that p73 is a tumor suppressor gene. Furthermore, the observation that viral oncoproteins discriminate between p53 and p73 might be taken as additional supporting evidence against p73 acting as a tumor suppressor protein. Clearly, additional studies will be required to determine the normal functions of p73 and to determine whether it plays any role in human carcinogenesis. Nonetheless, the studies performed to date suggest that p73 is rarely mutated in human cancer and that enforced expression of p73 would induce apoptosis in tumor cells. Thus, agents that induced the expression of p73 might be useful as antineoplastic drugs.


    CLONING OF P51
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
Several groups (2-6,84) have identified a third mammalian p53 homologue called variably Ket, p51, p40, p63, and p73L using a variety of methods including degenerate polymerase chain reaction and EST (i.e., expressed sequence tags) database searches. For simplicity, I will refer to this protein as p51. As was true for p73, cells contain different p51 transcripts as a result of alternative splicing as well as the use of multiple promoters (4,6). p51A and p51B correspond roughly to p73ß and p73{alpha}, respectively (4). Accordingly, both p51 isoforms contain putative transactivation, DNA-binding, and oligomerization domains. It is interesting that Yang et al. (6) identified p51 isoforms that lacked the N-terminal transactivation domain but could still bind to DNA. These forms were therefore capable of acting in a dominant-negative manner (6). p51 and p73 are more closely related to one another than either is to p53. p51 is highly related to a gene previously thought to be the squid homologue of p53.


    EXPRESSION OF P51
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
Rat p51 expression has been detected in tongue, skin, and thymus (3). Human p51 mRNA has been detected in a variety of human tissues, including skin, prostate, skeletal muscle, testes, and placenta (2,4-6). In such assays, some differences have been apparent when different studies are compared. These differences may be due, in part, to differences in the probes used. This is an important consideration, given the potential for tissue-specific alternative splicing as well as the possibility of cross-hybridization with p73 mRNA.


    FUNCTIONS OF P51
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
p51, like p73, can bind to canonical p53 DNA-binding sites in vitro and can activate transcription from p53-responsive promoters in vivo [(4,6); Marin C, Kaelin WG Jr: unpublished data]. In addition, p51 can induce apoptosis in p53-defective tumor cells (4,6).


    ALTERATIONS OF P51 IN HUMAN CANCERS
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
p51 maps to chromosome 3q27-8, a region that is deleted in some bladder cancers and amplified in some cervical, ovarian, and lung cancers (2,4-6). In one study (4), p51 mutations were detected in three of 101 tumors and tumor cell lines. Mutations were detected in one squamous cell carcinoma of the lung, one head and neck cancer cell line, and one cervical carcinoma cell line. All three mutations were located in the DNA-binding domain, and none of the corresponding tumors/tumor cell lines produced a wild-type p51 transcript. Thus, p51 mutations, although detectable, appear to be rare.


    FUTURE QUESTIONS
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
Why are there multiple p53 family members and why are p73 and p51, unlike p53, infrequently mutated in human cancers? Clearly, the answer to either one of these questions may shed light on the other. Several observations may be relevant here. First, p53 is ubiquitously expressed, whereas the expressions of p73 and p51 appear restricted to certain tissues. Second, p53 is induced by DNA damage, whereas p73 is not. It is possible that p53 has evolved specifically to protect cells from genotoxic insults and unprogrammed cellular proliferation, whereas p73 and p51 may have evolved to perform more tissue-specific roles. It will be important to determine what cellular signals activate p73 and p51. In particular, it will be important to determine whether oncogenes can induce p73 or p51 and, if so, whether this is mediated through modulation of HDM2 or p14ARF.

Another potential clue comes from two studies (85,86) that biochemically purified p53-like DNA-binding activities from p53 nullizygous cells. It was not shown whether these activities were due to p73 or p51 gene products. Nonetheless, these studies showed that p53-binding sites from different p53-responsive promoters differed in their ability to bind to p53 compared with these p53-like activities. In short, these studies raise the possibility that different p53 family members preferentially bind to and activate specific subsets of p53-responsive promoters. A related question is whether p53 family members bind to DNA exclusively as homodimers or whether, under certain circumstances, they might heteroligomerize.


    CONCLUSIONS
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 
p73 and p51 are two recently identified mammalian p53 homologues. Both proteins, at least when overproduced, can mimic the ability of p53 to bind to DNA, activate transcription, and induce apoptosis. Unlike p53, however, neither of these proteins appears to be frequently mutated in cancer, although additional studies are clearly indicated. The normal functions of these proteins remain to be elucidated. Nonetheless, the experiments performed to date suggest that activation of p73 or p51 expression might lead to apoptosis in tumor cells irrespective of their p53 status.


    REFERENCES
 Top
 Abstract
 Introduction
 Role of p53 in...
 p53 Function
 Cloning of p73
 Expression of p73
 Functions of p73
 Alterations of p73 in...
 Discrimination Between p73 and...
 Is p73 a Tumor...
 Cloning of p51
 Expression of p51
 Functions of p51
 Alterations of p51 in...
 Future Questions
 Conclusions
 References
 

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23 Leach FS, Tokino T, Meltzer P, Burrell M, Oliner JD, Smith S, et al. p53 mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res 1993;53(10 Suppl):2231-4.[Abstract]

24 Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 1998;92:725-34.[Medline]

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Manuscript received September 8, 1998; revised January 6, 1999; accepted February 1, 1999.


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