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).
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ABSTRACT |
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INTRODUCTION |
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ROLE OF P53 IN HUMAN CANCER |
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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.
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P53 FUNCTION |
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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).
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CLONING OF P73 |
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EXPRESSION OF P73 |
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FUNCTIONS OF P73 |
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Both p73 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).
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ALTERATIONS OF P73 IN HUMAN CANCER |
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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.
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DISCRIMINATION BETWEEN P73 AND P53 BY VIRAL ONCOPROTEINS |
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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.
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IS P73 A TUMOR SUPPRESSOR GENE? |
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CLONING OF P51 |
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EXPRESSION OF P51 |
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FUNCTIONS OF P51 |
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ALTERATIONS OF P51 IN HUMAN CANCERS |
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FUTURE QUESTIONS |
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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.
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CONCLUSIONS |
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Manuscript received September 8, 1998; revised January 6, 1999; accepted February 1, 1999.
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