P53 null mouse

Mdm2 deletion leads to stabilization of mutant p53RH and enhancement of the metastatic gain-of-function phenotype Terzian et al. This experiment is a proof of principle that stabilization of mutant p53 leads to gain-of-function phenotypes in vivo.

Because Mdm2 loss does not occur in human cancers quite the opposite , this experiment did not address what tumor-specific changes might regulate mutant p53 stability.

Thus, loss of p16 results in stabilization of wild-type p In combination with p53RH , p16 loss also stabilizes mutant p53RH in some cells and enhances the metastatic phenotype Terzian et al. Because Mdm2 and p16 loss stabilize and activate wild-type p53, these observations also indicate that mutant p53 is posttranslationally regulated like wild-type p53, such that the same signals that stabilize wild-type p53 may stabilize mutant p Thirdly, the analysis of p53 mutant mice also suggests that the dominant—negative phenotype associated with mutant p53 requires stabilization of mutant p However, once stabilized, mutant p53 has a longer half life than wild-type p53 and thus basically overwhelms wild-type p53 function Terzian et al.

Lastly, these p53 mutant alleles are true loss-of-function alleles as they have no wild-type p53 activity in numerous assays. It is now clear that multiple mechanisms cooperate to disrupt the p53 pathway in tumor development. The mouse has served as a model to directly examine some of those mechanisms.

A tumor suppressor gene is classically defined as the inheritance of one mutant allele and loss of the remaining wild-type allele loss of heterozygosity [LOH] during the process of tumor evolution Knudson These data indicate that although loss of both p53 alleles occurs in many tumors, loss of the wild-type p53 allele is not a requirement of tumorigenesis.

More importantly, the data imply that older mice have more time to acquire additional alterations that undermine the p53 pathway. What other changes contribute to inactivation of the p53 pathway? Many human tumors have high levels of p53 and Mdm2 Valentin-Vega et al. Clearly, increased Mdm2 and Mdm4 levels should inactivate the p53 pathway in tumorigenesis given what we know about the regulation of p53 by Mdm2 and Mdm4 in mice.

Data from mouse tumor models supports this hypothesis. An Mdm4 transgenic mouse also has a tumor phenotype that is exacerbated by p53 heterozygosity, emphasizing the cooperative nature of different molecular changes to inactivate the p53 pathway Xiong and Lozano, in prep.

A more careful analysis should be performed to determine if those tumors with stable mutant p53 are those that do not need to lose the wild-type p53 allele because of p53 inactivation via dominant—negative interactions with mutant p The timing of the second event that stabilizes mutant p53 may be the determining factor of whether tumor cells lose the wild-type p53 allele or not.

Altering p53 levels in vivo has consequences on organismal survival. Increased p53 activity results in cell-cycle arrest, senescence, early differentiation, or apoptotic cell death.

Survival of the organism depends on the extent of p53 activation, the cell type affected, and the timing of p53 activation. The ability of p53 to enact these functions is important for tumor suppression.

On the other hand, cells tolerate p53 loss extremely well. Cells lacking p53 are for the most part normal and do not necessarily become tumorigenic. Given the total number of cells in a mouse, it is most surprising that p53 -null mice do not develop many more tumors more rapidly.

The DNA damage that accumulates in a cell in the absence of p53 is likely insufficient for tumor formation. Cooperating changes in cell behavior seem to be required for tumor formation. For example, low dose ionizing radiation and carcinogen exposure contribute to an enhanced tumor phenotype in p53 -null mice Kemp et al.

Additionally, tissue and tumor specificity of cooperating events are different. Not all p53 targets are activated in one specific tissue or in response to the same signal in different tissues. The reactivation of p53 in tumors induces senescence in some and apoptosis in others. The cell and tissue-specific nature of p53 function needs to be addressed in more detail.

Determination of the events required for tumor maintenance must also be more fully explored. Lastly, the signals responsible for p53 stabilization in tumors must be understood more fully as it is stabilization that contributes to the gain-of-function and dominant—negative activities that cooperate in tumorigenesis.

The mouse has only begun to shed light on the tissue specificity, timing, and order of events that contribute to tumorigenesis in general, and to inactivation of p53 in particular. I thank Drs. Perry and J. Jackson for helpful discussions and criticism of this work.

Editors: Arnold J. Levine and David P. Additional Perspectives on The p53 Family available at www. National Center for Biotechnology Information , U. Cold Spring Harb Perspect Biol. Guillermina Lozano. Author information Copyright and License information Disclaimer. Anderson Cancer Center, Houston, Texas Correspondence: Email: gro. This article has been cited by other articles in PMC. Abstract Studies in mice have yielded invaluable insight into our understanding of the p53 pathway.

Open in a separate window. Figure 1. Figure 2. Too much or too little p53 in the mouse results in lethal phenotypes. Footnotes Editors: Arnold J. Lane Additional Perspectives on The p53 Family available at www. Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis.

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