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Reprints and Permissions. Soussi, T. TP an oncogene in disguise. Cell Death Differ 22, — Download citation. Received : 05 February Revised : 31 March Accepted : 01 April Published : 29 May Issue Date : August Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Oncogene Nature Communications Scientific Reports Advanced search.
Skip to main content Thank you for visiting nature. Download PDF. Subjects Tumour suppressors. Abstract The standard classification used to define the various cancer genes confines tumor protein p53 TP53 to the role of a tumor suppressor gene. Facts p53 mutants are among the most common protein variants expressed in cancer cells. Open Questions How does the diversity of oncogenic p53 variants contribute to the heterogeneity of the malignant phenotype? What is the contribution of p53 protein accumulation in human tumors to the GOF of mutant p53?
Is there a tissue specificity of mutant p53 GOF? What will be the best strategy to target oncogenic p53 mutants for improved cancer therapy? Pattern of TP53 mutations in human cancer: oncogenic hotspot mutant TP53 is one of the most frequently expressed protein variants in human cancer A unique feature of the TP53 gene compared with other tumor suppressor genes is its mode of inactivation.
Figure 1. Full size image. Figure 2. Figure 3. Mutant p53 heterogeneity: LOF and GOF Before addressing the various GOF activities of mutant p53, it is essential to discuss the reasons for one of the most striking features of mutant p53, namely p53 protein accumulation in tumor cells. Targeting mutant p53 for novel cancer therapy Many investigators have initiated efforts to develop novel strategies for pharmacological reactivation of mutant p53 in cancer cells. Figure 4.
Table 1 Classification of cancer mutations according to their consequences on protein activity Full size table. Conclusion In vitro , mouse in vivo and clinical studies all point toward the importance of selection for oncogenic p53 mutants in human tumors.
View author publications. Supplementary information. Supplementary Figure 1 PDF kb. Rights and permissions This work is licensed under a Creative Commons Attribution 4. About this article. Cite this article Soussi, T. Copy to clipboard. Joerger , Klas G. Shohdy , Panagiotis J. Vlachostergios , David C. Wilkes , Bhavneet Bhinder , Scott T.
Tagawa , David M. Nanus , Ana M. Molina , Himisha Beltran , Cora N. Sternberg , Samaneh Motanagh , Brian D. Chung , Mark A. Search Search articles by subject, keyword or author. In short, the advantages of having a mutant p53 to the growth and survival of the tumor cells can be classified as a mirror image of the tumor-suppressor functions of WT p53 Figure 2.
In this review, I will discuss the novel and acquired functions of mutant p53, specifically focusing on the DBD mutations. Figure 1. Mutant p53 functions during the evolution of a cancer cell. The schematic represents the general evolution of a normal cell into a transformed cell carcinoma , and the contexts in which mutant Mut p53 exerts its functions. Hence, in the intermediate stage, the mutant p53 co-exists with the wild-type WT p53, until the loss of the wild-type allele by loss-of-heterozygozity LOH.
Functionally, when p53 is unmutated, it can be activated and works as a tetramer. However, when one allele is mutated, there is reduced overall function resulting in haploinsufficieny, and also the dominant-negative effect of the mutant protein on the wild-type protein due to the formation of heterodimers please see text for details.
At the later stages when only the mutant p53 remains, it is unable to bind to canonical target sequences to turn on its targets, leading to loss of wild-type functions. In addition, mutant p53 acquires novel gain-of-functions to drive the growth, survival, and invasion of tumor cells. Figure 2. Mutant p53 — the contrived oncogene. The figure represents a mirror image of the functions of the wild-type and mutant p53 proteins. While wild-type p53 is a tumor suppressor, the mutant form represents not only a loss of these functions but also the acquisition of directly opposite functions.
Generally, in the early phases of cancer development, mutated p53 co-exists with the WT allele until the latter is lost due to LOH. In this co-existence phase, haploinsufficiency is a generally observed phenomenon associated with tumor development 5.
Several early studies indirectly illustrated this DN effect, especially through the overexpression of the mutant p53 in WT p53 expressing cells, or vice versa. Co-expression of WT p53 with mutant p53 was also shown to affect the conformation of the former into a mutant conformation due to co-translation with the mutant form 8.
Consequently, large efforts to analyze the DN effects of tumor-derived p53 mutants on the activation of several target genes have been undertaken in a systematic way using the yeast model, which was able to classify mutations as either dominant or recessive 13 , and has also led to the cataloging of p53 mutations based on the ability to regulate a large number of ptarget genes Although the DN phenomenon has been well demonstrated in a large series of studies, the question that remained was its relevance when mutant p53 is expressed from its endogenous locus.
Interestingly, while the DN effects were seen in some tissues, both on target gene activation and on cell survival, this was not the case in other cell types, as in primary fibroblasts in their growth, suggesting that the DN effect might be cell type, and possible stimulus dependent An interesting observation that emerges from all these studies with primary and transformed cells is that the DN effects on target gene activation and cell death are generally seen when cells are exposed to stress stimuli, including exposure to DNA-damaging agents, when p53 is activated and stabilized 15 , 16 , Thus, these data collectively surmise that the DN effect of mutant p53 is exhibited when the levels of the mutant p53 is elevated in acute stress conditions, and thus, may have a significant consequence when patients are treated with chemotherapy and radiotherapy.
Thus, acute p53 activation and DN effects of mutant p53 can be decoupled from the long-term effects of p53 in regulating tumor susceptibility. In this respect, early reports have suggested that at least three molecules of mutant p53 are required to impose a DN effect on one molecule of WT p53 7 , Given that stress signals are also able to further stabilize mutant p53, it is not unexpected that the ratio of mutant p53 to WT is significantly high, thereby leading to the observed DN effects.
In supporting this theory, reduction of the endogenous mutant p53 levels — using an hypomorphic mutant p53 knock-in mouse model — was indeed shown to alleviate the DN effects, both on target gene activation and cell death upon irradiation Thus, these observations consolidate the case for the requirement of a significant increase in mutant p53 levels — as seen in tumor cells, or in primary cells upon exposure to stress stimuli — for the manifestation of the DN effects, which could be ameliorated by reducing the mutant protein levels.
This implies that in a clinical setting, strategies that would reduce mutant p53 protein levels without an effect on WT p53 during therapy would lead to better efficacy of treatment and would be a future prospect that should be followed up. Mechanistically, there are a few modes of operation of the DN effect. The mutant p53, which itself is unable to specifically bind to the presponse elements, binds to the WT p53, thereby quenching it away from target gene promoters 6 , Alternatively, mutant p53 quenches away co-factors that are required for transactivation by the WT p53 bound to the promoter, thereby reducing the potency of the WT protein In addition, mutant p53 has been suggested to form aggregates, akin to those seen in protein misfolding diseases.
Herein, it has been suggested that the WT p53 protein is engulfed into mutant p53 fibrillar and granular aggregates, whereby the misfolded mutant protein sequesters the WT form, thus leading to inactivation of the WT function Whatever the mechanism may be, the underlying concept is that the ability of mutant p53 to bind to wild-p53 when in excess is causal to the DN effect, which could thus offer an avenue for exploitation for therapeutic benefit.
While there are currently no known ways of overcoming the DN effect, potential strategies that lead to the degradation of mutant p53 specifically without affecting the WT protein will be the way forward in ameliorating the DN effect. While the phenomenon of addiction to oncogenes has been well established 24 , mutated tumor suppressors have never been earlier reported to provide a survival advantage to tumor cells due to any novel acquired functions. In addition, indirect evidence for the requirement for mutant p53 for survival of cells in a phospholipase D-dependent manner was also noted This phenomenon is now well established in a large number of subsequent studies.
However, the causal mechanisms are still relatively elusive. In earlier studies, a role for transactivation by mutant p53 of cell growth regulation genes was suggested, as the transactivation deficient DBD p53 mutants were unable to provide a growth advantage In the other studies, mutant pmediated suppression of canonical ptarget genes was suggested to be the mechanism, which was ameliorated upon the silencing of mutant p53 expression, leading to cell death.
In this latter case, hypomethylation appeared to be involved, as trichostatin A — a HDAC inhibitor — was found to relief the mutant pdependent suppression Recent in vivo work in mice has also confirmed that destabilization of mutant p53 expression leads to apoptosis and reduction of tumor growth While addiction to mutant p53 appears to be critical for the survival of the cancer cell, the exact point at which they get addicted to mutant p53 is not understood.
While the transformed cells could be expected to become addicted to the presence of mutant p53 at the point in time of loss of the remaining WT p53 allele, it is likely that further events are required for this phenomenon to occur. Moreover, whether addiction to mutant p53 is a universal phenomenon in all cell types also requires further systematic analyses. Similar to mutant p53 addiction, the direct advantages conferred by the presence of the mutant p53 protein have been understood primarily through cell culture studies where isogenic cell lines without p53 expression have been used to analyze the effects of the overexpressed mutant p First direct evidence came from the overexpression of several human e.
While this was the first case of evaluating the effects of the mutant version of the natural tumor suppressor, earlier studies using a mutant p53 — at that time thought to be the natural existing form prior to the knowledge that p53 is actually a tumor suppressor — also showed growth advantage due to its overexpression In addition, there are multiple other parameters associated with genomic instability that were noted due to the overexpression of mutant p53, including gene and centrosome amplification and disruption of spindle checkpoint 34 — Consistently, overexpression of mutant p53 also led to resistance to death induced by a variety of chemotherapeutic drugs and DNA-damaging agents 38 — 41 , as well as by anoikis More recently, expression of mutant p53 was also shown to enhance the Warburg effect on cancer cells, promoting GLUT1 translocation to the plasma membrane, and thus enhancing glucose uptake Not unexpectedly, many studies have also evaluated if the expression of mutant p53 would enhance cellular invasion and migration and found that to be the case in a variety of 2D and 3D cellular systems 18 , 44 — At the organismal level where mutant p53 is expressed from its own locus — reflecting the status in human cancer conditions — GOF properties were also noted with the generation of the p53 mutant knock-in mice.
The initial data demonstrated that the p53 RH mice equivalent to human RH were more tumor prone with more carcinomas — reflecting a change in tumor spectrum. They also had increased metastasis compared to the p53 null mice, in the absence of Mdm2, which leads to increased mutant p53 levels 15 , Further studies have cemented these findings, where the presence of the RH mutant p53 protein conferred significant growth and metastatic propensity to tumors compared to the loss of p53, in several oncogene-induced models, including Ras and APC, in a variety of tumor types such as lung and pancreatic ductal adenocarcinomas 46 , 48 , Similar observations were also noted with other mutations, such as the RH and RH in breast and lung cancer models 50 , These data mooted the idea that all mutant p53 would have GOF properties, and that this may depend on the stabilization of the mutant p53 in the cancer cell context, as normal untransformed tissues from the mutant p53 bearing mice did not have significant growth advantage and did not display increased steady-state levels of the mutant protein However, this theory came under challenge through the analyses of another hot-spot p53 mutant knock-in mouse strain the RS, equivalent to human RS.
In this case, the RS mutant mice did not display any tumor latency difference or metastatic advantage even in the absence of Mdm2 Similar results were also seen with other hot-spot mutant knock-in mice strains, in which the RQ had a strong GOF phenotype in contrast to the GS mutant 52 , collectively alluding the fact that GOF may not be a universal phenomenon, and that elevation of mutant p53 levels may not be sufficient for their exhibition. Nonetheless, as observed in the cell culture-based studies, there was a propensity to have more hematopoitic or mesenchymal stem cells in the RQ mutant p53 knock-in mice, indicative of an effect of mutant p53 on the plasticity of the stem cell population Besides the effects on tumor metastasis and aggressiveness, the effects of mutant p53 on several other aspects of physiology have been noted using the knock-in mice strains.
For instance, there was increased inflammation and tissue damage, primarily due to upregulation of inflammatory cytokines that were induced by mutant pmediated prolonged activation of NFKB signaling Angiogenesis was also shown to be enhanced due to mutant p53 expression, through the activation of ID4 expression in cell culture studies These studies collectively indicate that expression of mutant p53 in tumor cells, as seen in the case with human cancers, as well as in normal tissues as analyzed from animal studies, has far-reaching consequences on organimsal physiology.
While enormous amounts of data from cellular systems and animal models highlight the existence of GOFs of mutant p53, albeit to varying degrees perhaps depending on several contextual factors, the main question is the relevance of this phenomenon in humans.
A noteworthy point is that humans generally do not carry a mutant p53 allele in non-transformed tissues, except in the case of the Li—Fraumeni patients. Thus, the GOF properties would be of relevance in the large majority of tumors that eventually retain only the mutant allele. On the other hand, the Li—Fraumeni patients would be expected to have one allele that is WT in all untransformed tissues, except in cases where LOH would result in or occur with other transforming events that lead to tumorigenesis.
Thus, even in the Li—Fraumeni group, the GOFs and addiction to mutant p53 would be a phenomenon that would be of relevance primarily in the cancer cell context.
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