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(The FASEB Journal. 2000;14:1901-1907.)
© 2000 FASEB

p53 from complexity to simplicity: mutant p53 stabilization, gain-of-function, and dominant-negative effect

MIKHAIL V. BLAGOSKLONNY1

Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA

1Correspondence: Medicine Branch, NCI, NIH, Bldg. 10, Room 13 N 226, Bethesda, MD, 20892, USA. E-mail: mikhailb{at}box-m.nih.gov


   ABSTRACT
TOP
 ABSTRACT
FUNCTIONS OF WILD-TYPE P53...
 p53 STABILIZATION AS A...
 GAIN-OF-FUNCTION AS UNBALANCED...
 APPLICATIONS TO CANCER THERAPY
 REFERENCES
 
Increasing the complexity of their models, p53s are stabilized either in order to function (wt p53) or due to the loss of function (mutant p53) with acquiring a mysterious prion-like ability to drive the normal p53 into the abnormal conformation to gain new functions. As already recognized, the loss of trans-activating function leads to a stabilization of mutant p53 because of the disappearance of the p53-inducible proteins, which otherwise directly (Mdm-2) or indirectly (p21) target p53 for degradation. Simplifying further, I will discuss that the loss of function results in a dominant-negative effect and gain-of-function (a dominant-positive effect). Thus, mutant p53 lacking trans-activation function nevertheless may retain the ability to repress transcription due to its competition with numerous transcription factors for their coactivators. When mutant p53 competes with wt p53, the inhibition of the wt p53-dependent transcription is perceived as a dominant-negative effect. Just like trans-repression, a dominant-negative effect requires an excess of p53 and, therefore, a ‘dominant’-negative effect is not dominant. Furthermore, the stabilization of an endogenous mt p53 due to the loss of wt functions cannot occur in the presence of the wt p53 allele. Given the inability of mutant p53 to accumulate in the presence of wt p53, a dominant-negative effect does not naturally occur and, not surprisingly, heterozygous mt/wt cells are rare. The detection of a dominant-negative effect simply indicates that mutant p53 indeed has lost its function. Last, since mutant p53 loses some or most but not all activities and accumulates in the absence of wt allele, gain-of-function can be considered as an exaggeration of the remaining functions. Applications to cancer therapy are discussed.—Blagosklonny, M. V. p53 from complexity to simplicity: mutant p53 stabilization, gain-of-function, and dominant-negative effect.


Key Words: prion • dysfunction • cancer therapy • trans-activating function


   FUNCTIONS OF WILD-TYPE P53 AND MYSTERIES OF MUTANT p53
TOP
 ABSTRACT
 FUNCTIONS OF WILD-TYPE P53...
p53 STABILIZATION AS A...
 GAIN-OF-FUNCTION AS UNBALANCED...
 APPLICATIONS TO CANCER THERAPY
 REFERENCES
 
AS THE MOST intensely studied protein, p53 possesses myriad potential functions while hundreds of mutations bring about losses and gains of functions further diversifying p53 behavior. This diversity along with divergent signals that modulate p53 further increases the complexity of p53 (1 2 3) . In order to simplify, I will discuss that most properties of mutant p53s (mt p53s) can be explained by one single cause: loss of trans-activating function.

The p53 tumor suppressor is a transcription factor involved in cell cycle checkpoints, apoptosis, and genomic stability (4 5 6 7 8 9) . p53, however, has activities that are independent from the trans-activation. Thus, p53 can trans-repress viral and cellular promoters and can induce a transcription-independent apoptosis (10 11 12 13 14 15 16 17 18) . Oncogenic mutations in p53 that abrogate its trans-activating function are accompanied by three puzzling phenomena.

Dominant-negative effect or the ability of mt p53 to inactivate wild-type 53 (wt p53)
The ability mutant p53 to drive wt p53 to a mutant conformation is considered the mechanism of the dominant-negative (DN) effect. It is interesting that prions, infectious proteins, propagate by a similar mechanism even though mutant p53 is not an infectious particle.

Gain-of-function
Gain-of-function (dominant-positive effect) is the ability of mt p53 to acquire novel functions (19) . In contrast to the DN effect, gain-of-function occurs in the absence of second wt p53 allele.

Stabilization of mutant p53 proteins
Originally, p53 was discovered due to stabilization of p53 protein in the presence of T antigen (20 , 21) . For a long time it was assumed that mutant p53 protein is intrinsically stable and therefore overexpression of mutant p53 is a simple basis for the dominance of mutant over wild-type p53. As I will discuss, stabilization of mutant p53 cannot occur in the presence of wt p53 and therefore the dominant-negative effect is not dominant.


   p53 STABILIZATION AS A MARK OF DYSFUNCTION
TOP
 ABSTRACT
 FUNCTIONS OF WILD-TYPE P53...
 p53 STABILIZATION AS A...
GAIN-OF-FUNCTION AS UNBALANCED...
 APPLICATIONS TO CANCER THERAPY
 REFERENCES
 
In internal medicine, it is known that the enlargement of organs—for example, enlarged heart, spleen, liver, or kidney—is a common symptom of their dysfunction. Nonetheless, the enlargement of the organ is the result of its dysfunction, not the cause of dysfunction. The organ simply attempts to compensate for insufficient function by increasing its size. This analogy is useful for understanding a mutant (disabled) p53.

The stabilization of a disabled p53 and thus its overexpression enabled the discovery of p53 20 years ago (20 , 21) . It was recognized later that activating mutations within the p53 gene caused stabilization of the p53 protein. Finally, the concepts of loss of function as a cause of mt p53 stabilization had been proposed from different perspectives (22 23 24 25) .

The activity of wt p53 depends mostly on the amount rather than modifications of the p53 protein, because overexpression of ectopic wt p53 maximally induces p53-responsive genes (see, for example, ref 26 ). Normally, wt p53 protein is rapidly degraded by the proteasome and therefore has a short half-life. Degradation of wt p53 is regulated by a feedback control of its trans-activating function (25) . Thus, as shown in Fig. 1A , wt p53 induces Mdm-2, which in turn targets p53 for degradation (22 , 23) . Phosphorylation of wt p53 (27 , 28) after DNA damage prevents the interaction between Mdm-2 and p53, although the significance of phosphorylation is disputed (29 , 30 . Nevertheless, DNA damage prevents interaction of mdm-2 with p53 (2) and thus prevents p53 degradation leading to the accumulation of both p53 and p53-responsive proteins (Fig. 1B ). When mutant p53 loses its trans-activating function, it cannot induce Mdm-2 and therefore is not degraded (Fig. 1C ). This mechanism is also responsible for the stabilization of wt p53 caused by inhibitors of transcription (31 , 32) .



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  		Figure 1. Regulation of p53 stability. A) Wild-type p53 (wt) transcriptionally induces mdm-2, which in turn targets p53 to degradation. B) DNA damage prevents wt p53 and mdm-2 interaction. wt p53 accumulates and trans-activates p53-dependent genes (e.g., mdm-2). C) Mutant p53 (mut) cannot trans-activate mdm-2: p53 is not degraded and it is accumulated. Also, it is the mechanism of wt p53 accumulation caused by inhibitors of transcription. D) In the presence of wt p53 allele, mutant p53 is targeted to degradation by wt p53-induced mdm-2.

Mdm-2 is an essential feedback regulator of p53 degradation because the Mdm-2 knockout is lethal and is corrected by the p53 knockout (33) . However, other p53-induced proteins may indirectly regulate p53 stability. For instance, by affecting the E2F/ARF/Mdm-2 pathway (34) , p21 may decrease levels of p53. Like p53, many p53-dependent proteins (p21, Mdm-2, and Bax) are degraded by the proteasome (35 36 37 38) . This explains the paradoxical down-regulation of mutant p53 after inhibition of the proteasome associated with accumulation of Mdm-2 and p21 (31) . A cell cannot discriminate what causes the induction of the p53-dependent proteins. It could be mutant p53 that retains some functions, non-p53 stimuli, or wt p53 allele. Therefore, in the presence of wt p53, mutant p53 cannot accumulate because both p53 proteins are targeted for degradation by Mdm-2, which is induced by wt p53 allele (Fig. 1D ). For example, heterozygote Li-Fraumeni syndrome cells contain an equal amount of wt p53 and mt p53 (39) , and mutations at codon 248 are stabilizing only in the absence of the wild-type p53 (40) , indicating lack of mt p53 stabilization in the presence of wt p53.

Dominant-negative effect as a competition without function
In contrast to stabilization of mutant p53, the dominant-negative effect has yet to be adequately explained. There are two tempting elegant notions that nevertheless may preclude the explanation of the mechanism of a dominant-negative effect.

First, a flexibility of p53 protein conformation coupled with the ability of mutant p53 to drive wt p53 into mutant conformation during cotranslation in vitro provides a simple explanation for the dominant-negative effect (41 , 42) . In a broader sense, this represents a prion (Pr) model (Fig. 2A vs. B ), even though such comparisons have been never made. Infamous recently by the mad cow disease, a Pr is an infectious protein with abnormal (mutant) conformation that propagates by forcing a normal protein to adapt mutant conformation (43) . According to the conformational model, mutant p53 changes conformation of normal (wt) p53 protein in a prion-like fashion (Fig. 2B ). Although this conformational model of a dominant-negative effect dictates a prion-like behavior of mutant p53, mutant p53 actually possess no characteristics of an infectious protein and of course mutant p53 cannot propagate. Furthermore, the prion-like model cannot explain the following observations: 1) an excess of mt p53 is required to affect wt p53 (44 45 46 47) ; 2) mutant p53 proteins that have a wt conformation still able to exert the dominant-negative effect (48) ; and 3) direct interaction between wt and mt p53 (hetero-oligomerization) is not always necessary for the dominant-negative effect (49) and trans-activation by the oligomerization-defective mutant can be inhibited by the transforming mutant p53–175H (50) .



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  		Figure 2. Two models of dominant-negative effect. A, B) Prion-like models. Pr, prion; mut, mutant p53; wt, wt p53. C, D) Trans-repression-like models. CF, cofactor.

The second tempting idea is that a dominance of mutant p53 may occur through its stabilization. As discussed, however, the stabilization of mt p53 cannot take place until the function of wt p53 (second allele) is lost. Therefore, the stabilization plays no role in the dominant-negative effect because mt p53 cannot become unilaterally stable in the presence of wt p53 (Fig. 1D ).

According to the ‘two-hit’ model, the inactivation of both alleles of tumor suppressor genes is required for cancer initiation (51) . In contrast, the notion of a dominant mutation in the first p53 allele that leads to a conformational inactivation of the second p53 rejects the ‘two hit’ model. In reality, however, endogenous mutant p53 does not inactivate wt p53. Nevertheless, the ability of mutant p53s that are isolated from cancer cells to exert the dominant-negative effect (52 , 53) indicates its selective advantage. A simple explanation of the selective advantage of the dominant-negative effect is that it reflects another trait: loss of trans-activating function.

Thus, the loss of trans-activation function with retaining trans-repression activity may determine dominant-negative effect. Transcription factors require cofactors—for example, p300/CBP (54 55 56) . In contrast to trans-activation, trans-repression by p53 does not require DNA binding. Trans-repression occurs at higher levels of p53 and can be explained by the competition with transcription factors for coactivators (57 58 59 60 61) . Wt p53 has been shown to inhibit transcription from several viral and cellular promoters without p53 binding sites (Fig. 2C ). Although mutant p53s lose DNA binding ability, they do not necessarily lose the ability to interact with cofactors of transcription. Therefore, loss of DNA binding does not necessarily affect p53’s ability to trans-repress. By interacting with cofactors, mutant p53 can compete not only with another transcription factors, but also with wt p53; mutant p53 may compete with wt p53. When artificially overexpressed, mutant p53 can trans-repress wt p53-mediated transcription, described as dominant-negative effect (Fig. 2C , 2D ).

Noteworthy, the p53 mutants that retain their trans-activation function do not exhibit dominant-negative effects (Fig. 3 ). Mutant p53 can lose the ability to activate some but not other promoters. For example, many mutant p53 retain the ability to trans-activate p21 but not Bax promoter constructs (57 , 62 63 64 65) . This predicts that the dominant-negative effect is promoter selective; in fact, mutants that selectively lose the ability to trans-activate the Bax promoter exerted the DN effect against Bax but not against p21 promoter constructs.



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  		Figure 3. Loss-of-function and dominant-negative (DN) effect. Mutant p53 that retains the ability to trans-activate the p21 but not Bax. A) Exogenous mutant p53 (mut) out-competes wt p53 (wt) for a cofactor (CF), but it trans-activates p21: DN effect is not observed. B) Exogenous mutant p53 out-competes wt p53 for a cofactor, but it does not trans-activate Bax; DN effect is observed.

As a consequence of the loss-of-function, dominant-negative effect:

Dominant-negative effect is not dominant
Mutant p53 is not dominant over endogenous wild-type p53 (44 45 46 47) . Equal transcription of wild-type and mutant p53 results in the situation whereby mutant protein is unable to suppress wild-type function. This explains why the inactivation of both p53 alleles is required for cancer development (66) . Also, an excess of wt p53 is dominant over mutant p53. Therefore, a ‘dominant-negative effect’ is not dominant, as initially proposed, but it actually is a competitive-negative effect.

Although mutant 135Val p53 allele may act in mice in a dominant-negative manner in the presence of wt p53 (67) , multiple copies of the mt p53 gene were used. Since only one copy of mutant gene is present in human cancer cells, the second allele is almost always lost or silenced at the protein level (68 , 69) . Although rare, why do heterozygous cells still exist? This may be a step toward a loss of the second allele, or the second allele may be functionally inactivated without loss. Furthermore, 50% cancers and cancer cell lines do not lose wt p53 and do not acquire mutations. These cell lines may be indifferent for p53 status or even may favor wt p53. Since loss of p53 increase rate of mutations or genomic instability (70) , one can envision that wt p53 may provide advantages in certain conditions. In contrast, losing p53 under adverse conditions may become advantageous by increasing genomic instability, allowing adaptation to new conditions (71) . As the bottom line, if a cell must lose wt p53 function, the inactivation of both p53 will occur without relying on the dominant-negative effect. Loss of one p53 allele and mutation of the remaining copy occur in human malignancies (72 , 73) .

Loss-of-function mutant p53s are DN
As stabilization of mt p53 is a consequence of the loss of trans-activating function (25 , 74) , the dominant-negative effect is also a consequence of the loss of trans-activating function. This simplified approach explains why all transcriptionally inactive p53 mutants isolated in yeast have been DN, even though the DN property seemingly was not a requirement for mutant isolation (53) . These two properties cannot be dissociated. This is supported by the observation that trans-dominance is a common property of p53 missense mutations rather than a specific criterion for selection in human tumors (53) . Dominant-negative mutants are the most common mutants found in human cancer (1) , simply reflecting loss of p53 transcriptional activity. Furthermore, it has been shown that the dominant-negative p53 mutants accelerate a development and/or a growth of glioblastoma anlagen (75) . I suggest that other mutants are asymptomatic, because they retain function. Such mutations are epiphenomenal, not casual.


   GAIN-OF-FUNCTION AS UNBALANCED DYSFUNCTION
TOP
 ABSTRACT
 FUNCTIONS OF WILD-TYPE P53...
 p53 STABILIZATION AS A...
 GAIN-OF-FUNCTION AS UNBALANCED...
APPLICATIONS TO CANCER THERAPY
 REFERENCES
 
As discussed above, mutant p53 loses trans-activating functions and may exert the dominant-negative effect as a result of loss of function. In addition, it has been described that mutant p53 may possess novel functions not seen in wt p53, described as gain-of function or the dominant-positive effect (19 , 76) . For instance, multiple copies of mutant 135Val p53 allele accelerates tumor development in normal but not in p53-deficient mice (67) . How can random mutations in the p53 gene cause functions?

A simple answer is that loss of function leads to gain of functions when p53 loses some but not all wt functions. Mutations occur in the DNA binding domain or the domain that determines the structure of DNA binding domain. This results in the inability to activate some p53-dependent promoters. For example, whereas wt p53 trans-activate both Bax (77) and p21 (26) , mutant p53 can lose the ability to trans-activate Bax but not the p21 promoter (62 , 63) . Bax and p21 often exert opposite effects on sensitivity to chemotherapy (Fig. 4A ). For example, whereas Bax increases the sensitivity to paclitaxel, p21 decreases the sensitivity (78) , and therefore total loss of p53 function may have no effect. However, selective loss of the ability to trans-activate Bax will change the balance and leaving p21 without counterbalance (Fig. 4B ). Furthermore, if mt p53 loses the ability to activate the Mdm-2 promoter, this will result in p53 stabilization (Fig. 4C ). For example, E1A inhibits the Mdm-2 trans-activation, which resulted in high levels of p53, without affecting the expression of p21 or Bax, (79) . Since the level of mutant p53 protein represents the highest level that can be achieved by wild-type p53 in a cell after DNA damage (31) , nontranscriptional activities may be grossly exaggerated (80) ; this may be interpreted as a gain-of-function. While most of ‘gain’-of-functions may in fact be ‘imbalanced’ function, it is impossible to rule out that certain mutations result in the acquisition of functions that are completely absent in wt p53. Further studies may include or exclude such possibilities.



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  		Figure 4. Loss- and gain-of function. A) Wt p53 induces Bax, p21 and other proteins. Total loss of wt p53 would not affect a balance between Bax and p21. B) Loss of ability to trans-activate Bax leads to the imbalance that may be perceived as gain-of-function. C) Loss of ability to trans-activate Mdm-2 leads to p53 stabilization and further imbalance, with exaggerated nontranscriptional effects that are perceived as gain-of-function


   APPLICATIONS TO CANCER THERAPY
TOP
 ABSTRACT
 FUNCTIONS OF WILD-TYPE P53...
 p53 STABILIZATION AS A...
 GAIN-OF-FUNCTION AS UNBALANCED...
 APPLICATIONS TO CANCER THERAPY
REFERENCES
 
Mutations of p53 provide both challenges and opportunities in cancer therapy (81 82 83) . Pharmacological depletion of mutant p53 is achievable (84) . Lack of dominance of mutant p53 over wt p53 makes it possible to transfer wt p53 by adenovirus vectors. The most promising approach is a restoration of normal functions of mutant p53 (85 , 86) . Not only may it not affect normal cells with wt p53, but also it may be especially toxic for cancer cells with mutant p53 because of a sudden acquisition of function by stable and therefore overexpressed mutant p53. Once the function is restored, p53 will be rapidly degraded. Taking into account transcriptional activation of Bax, KILLER, and TRAIL genes by wt p53 (77 , 87 , 88) , such interventions will have acute effect and may be combined with other drugs.

Alternatively, instead of its restoration, loss of p53 function in cancer cells can be exploited for therapeutic advantages. Thus, pharmacological inactivation of wt p53 in normal cells may be protective against radiation (89) . Future development of the Mdm-2 mimicking or the Mdm-2-inducing agents may be needed for nontoxic regimes. An opposite approach of selective cytoprotection of normal cells can be based on the wt p53 checkpoints that are lost in cancer (90) . Thus, low doses of DNA damage by inducing p53-dependent growth arrest protected cells against cytotoxicity of antimitotic drugs (91) .The latter approach will benefit from the development of nontoxic agents that inhibit Mdm-2-dependent degradation of p53.


   REFERENCES
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 ABSTRACT
 FUNCTIONS OF WILD-TYPE P53...
 p53 STABILIZATION AS A...
 GAIN-OF-FUNCTION AS UNBALANCED...
 APPLICATIONS TO CANCER THERAPY
 REFERENCES
 

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