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[Cancer Research 62, 3221-3225, June 1, 2002]
© 2002 American Association for Cancer Research

Molecular Biology and Genetics

mdmx Is a Negative Regulator of p53 Activity in Vivo

Rick A. Finch, Dorit B. Donoviel, David Potter, Min Shi, Amy Fan, Deon D. Freed, Ching-yun Wang, Brian P. Zambrowicz, Ramiro Ramirez-Solis, Arthur T. Sands and Nan Zhang1

Lexicon Genetics, Incorporated, The Woodlands, Texas 77381


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
Regulation of p53 protein activity is required for normal embryogenesis, tumor suppression, and cellular response to DNA damage. Here we report that loss of mdmx, a p53-binding protein, results in midgestational embryo lethality, a phenotype that is completely rescued by the absence of p53. Mice homozygous for both mdmx and p53 null mutations are viable and appear developmentally normal. Fibroblasts derived from embryos with reduced mdmx expression demonstrate a decreased growth rate and increased UV-induced apoptosis compared with wild-type cells and contain elevated levels of p53 and several p53 target proteins including the proapoptotic bax protein. These observations demonstrate that mdmx functions as a critical negative regulator of p53 in vivo.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
mdmx (also known as mdm4) is a p53-binding protein with structural similarity to the proto-oncoprotein mdm2 (1) . p53 binding by mdm2 results in a masking of the p53 transactivation domain (2, 3, 4) and the subsequent targeting of p53 for proteasome-dependent degradation (5 , 6) . Thus, mdm2 is a major negative regulator of p53 function (see Ref. 7 for a recent review). mdm2 null embryos die in utero; however, this embryonic lethality can be overcome by deletion of the functional p53 gene product (8 , 9) . mdmx also inhibits p53 function through suppression of p53-dependent transactivation of target genes; yet mdmx has been shown to protect p53 from mdm2-mediated degradation (10 , 11) . In contrast to mdm2, the levels of mdmx expression do not change in cultured cells exposed to UV irradiation (1) , suggesting that the activation of these two p53 regulators is controlled by different pathways. Given the central role of p53 in human cancer, a better understanding of the regulation of the p53 pathway may uncover new cancer therapeutic targets and strategies.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS AND DISCUSSION
 REFERENCES
 
Genotyping.
In some studies, determination of the genotype of mice at the mdmx locus was performed by using a Southern blotting method to compare the intensities on autoradiograms of 1.5-kb SacI fragments hybridizing to a neomycin phosphotransferase-specific probe. This strategy enabled discrimination of zero, one, or two gene disruptions, representing (+/+), (+/-), and (-/-) mice, respectively, at any trapped genetic locus. The c-src tyrosine kinase gene was probed as a normalization control.

A Southern blotting RFLP strategy was used for analysis of the mdmx gene status in the context of disrupted p53. A probe directed to the genomic sequence between the mdmx coding sequence in the 5' region of the trapped sequence tag and the 3' end of the 3'-long terminal repeat in the trapping vector was generated using PCR. This 500-bp probe recognizes SacI fragments of approximately 10 and 5.5 kb in wild-type and disrupted mdmx alleles, respectively.

p53 genotyping was performed using a multiplex PCR-based strategy developed by Timme and Thompson (12) . A 320-bp PCR product is produced from the wild-type p53 allele, and a 150-bp PCR product is produced from the disrupted p53 allele.

Northern Blot Analysis of mdmx.
Total cellular RNA was isolated from cultured cells using TRIzol reagent (Life Sciences, Gaithersburg, MD). An [{alpha}32P]dCTP random primer-labeled probe corresponding to nucleotides 1–298 of the mouse mdmx cDNA was used for Northern hybridization.

Apoptosis Assay.
Apoptosis was quantified by two methods: (a) using a Cell Death Detection ELISA kit (Roche Diagnostics Corp., Indianapolis, IN), which is a photometric enzyme-immunoassay for quantitation of histone-associated DNA fragments (nucleosomal DNA) in the cytoplasm after apoptosis induction; and (b) assessment of the morphological appearance of acridine orange/ethidium bromide-stained cells using fluorescence microscopy (13 , 14) .

Western Blotting.
Total cell lysates were prepared in Laemmli buffer and subjected to Western blot analysis using p53-, bax-1-, mdm2-, p21-, and thrombospondin I-specific antibodies (Santa Cruz Biotechnology, Santa Cruz, CA).


   RESULTS AND DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
REFERENCES
 
We now report the use of a large-scale reverse genetic approach based on genome-wide gene trapping technology (15 , 16) to demonstrate the role of the mdmx gene in the regulation of the p53 tumor suppressor protein in vivo. We identified an ES2 cell clone containing a single gene trap insertion in the mdmx gene using a bioinformatic screen of the sequence-tagged ES cell clones in the OmniBank library. This allowed for the rapid development and phenotypic analysis of a knockout mouse line. As judged by sequence alignment, the retroviral insertion is in the forward direction near the 5'-end of the coding region of the mdmx cDNA, 1–2 codons downstream of the ATG start site. Mice heterozygous for the mdmx disruption (mdmx1) were mated, and their offspring were genotyped at the mdmx locus. Of 61 offspring from nine litters representing five separate crosses, 24 were wild-type, 37 were mdmx1/ +, and none were homozygotic for mdmx disruption, indicating that expression of mdmx is required for normal embryo development. mdmx1/mdmx1 embryos died between E10 and E12 and were resorbed by E13.5. The lethality may be attributable to cardiovascular defects or partial chorioallantoic fusion, as suggested by the pooling of blood in the pericardial cavity or collapsed allantois, respectively (not shown). mdmx1/mdmx1 embryos exhibited cephalic structures that were reduced in size, most notably the telencephalon (Fig. 1Citation , compare A and B). Although the hindbrain/midbrain and forebrain/midbrain boundaries appear to form, these looked abnormal in some of the embryos (Fig. 1, C and D)Citation .



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  		Fig. 1. Cephalic abnormalities in mdmx1/mdmx1 embryos. A, wild-type E11.5 embryo (littermate of embryo shown in B). B, mdmx1/mdmx1 embryo exhibiting a telencephalon that is reduced in size. C, close-up of the head of the embryo shown in B, showing an abnormal hindbrain-midbrain boundary. D, close-up of the head of the embryo shown in A.

 
To study the effects of mdmx on cell proliferation, apoptosis, and gene expression, we generated mouse embryonic fibroblasts from E14 embryos produced by crossing mdmx1/+ mice (17) . We were unable to recover any lines of mdmx1/mdmx1 fibroblasts from early embryos because of a severe defect in the ability of cells that are homozygous for the mutation to proliferate in culture. However, we were successful in recovering a large number of embryonic fibroblast lines that were heterozygous for the mdmx1 allele as well as developmentally matched, wild-type control fibroblasts. mdmx mRNA was not abundantly expressed in embryonic fibroblasts and therefore did not produce a strong signal by Northern hybridization. Even so, Northern blot analysis did confirm a lower level of mdmx mRNA in mdmx1/+ embryonic fibroblasts than in wild-type fibroblasts (Fig. 2A)Citation . This decrease in mdmx expression was correlated with a markedly reduced cell proliferation rate (Fig. 2B)Citation . We also observed occurrence of replicative senescence in the mdmx1/+ cells after fewer passages in culture compared with wild-type cells. Thus, further comparisons of wild-type and mdmx1/+ fibroblasts were made using cells that had undergone fewer than five passages in culture.



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  		Fig. 2. A, Northern blot analysis of mdmx in mdmx1/+ and wild-type fibroblasts. Arrows, mdmx transcripts. The ethidium bromide-stained gel shows approximately equal loading. B, growth rate comparison of wild-type and mdmx1/+ fibroblasts. Bars, SD.

 
To confirm the influence of the mdmx deficiency on p53-dependent processes, we investigated the induction of apoptosis in these fibroblasts after exposure to low dosages of UV irradiation. Sixteen h after exposure to UV irradiation, mdmx1/+ fibroblasts with reduced mdmx expression exhibited an increased occurrence of apoptosis compared with wild-type cells as determined by the increased number of cytoplasmic histone-associated DNA fragments (Fig. 3A)Citation . Fluorescence microscopic assessment of the morphology of acridine orange/ethidium bromide-stained fibroblasts showed that nonirradiated wild-type and mdmx1/+ cultures contained few apoptotic cells (1.0 ± 0.6% and 1.0 ± 0.5%, respectively). Consistent with the results shown in Fig. 3ACitation , after irradiation, a greater percentage of apoptotic cells was observed in the mdmx1/+ cultures (11.1 ± 0.9%) than in the wild-type cultures (5.9 ± 1.8%).



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  		Fig. 3. A, apoptosis in embryonic fibroblasts after exposure to UV irradiation (20 J/cm2). Absorbance (405–495 nm) reflects the presence of histone-associated DNA fragments in the cytoplasm after apoptosis induction. B, Western blot analysis of p53 and the protein products of selected p53-responsive genes in mdmx1/+ and wild-type fibroblasts. A duplicate gel was stained with Coomassie Brilliant Blue (CBB) to show equal loading.

 
We also found that p53 protein levels were notably higher in nonirradiated mdmx1/+ fibroblasts than in wild-type cells (Fig. 3B)Citation , indicating that the presence of mdmx reduces p53 protein levels. It has been shown that proapoptotic mediators such as bax and bak are up-regulated when p53 is overexpressed in cancer cells (18) , and that p53-induced apoptosis requires activation of the expression of downstream target genes such as bax (19) . Consistent with the increased p53 levels, mdmx1/+ fibroblasts were found to contain elevated levels of the protein products of several p53-responsive genes including bax (Fig. 3B)Citation . The levels of all p53-responsive gene products examined (e.g., p21) were not notably increased in mdmx1/+ fibroblasts, however. Interestingly, the amount of mdm2, a mediator of p53 degradation, was increased in the mdmx-deficient cells. It is possible that mdmx is required to cooperate with mdm2 to control levels of p53 protein and prevent excessive activation of p53-dependent signaling. Taken together, these results support the hypothesis that the presence of mdmx can reduce p53-mediated apoptotic responses as well as modulate downstream targets of p53.

The increased steady-state level of p53 protein in mdmx1/+ fibroblasts was not attributable to stabilization of p53 protein with reduction in mdmx. Laser densitometric scanning of p53 Western blots produced from mdmx1/+ and wild-type cells incubated with cycloheximide showed no significant change in p53 protein half-life (Fig. 4A)Citation . Northern analysis revealed increased steady-state p53 mRNA in the mdmx1/+ fibroblasts compared with wild type (Fig. 4B)Citation , suggesting that the increased p53 protein level in the mdmx1/+ cells results from increased p53 mRNA, either directly or indirectly as a result of lowered mdmx levels.



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  		Fig. 4. A, top, Western blot analysis of p53 in wild-type and mdmx1/+ fibroblasts after addition of cycloheximide (CHX, 40 µM). *, time, minutes after addition of cycloheximide. A, bottom, quantitative analysis of p53 protein. Autoradiograms were subjected to laser densitometric scanning for semiquantitative assessment of the amount of p53 protein. B, Northern blot analysis of p53 expression in wild-type and mdmx1/+ fibroblasts. The ethidium bromide-stained gel shows approximately equal loading.

 
To determine whether mdmx regulates p53 in vivo, we investigated the consequences of mdmx loss in mice null for p53. We crossed mdmx1/+ mice with mice heterozygous for a p53 mutation to generate mice heterozygotic for both p53 and mdmx. Of 99 viable offspring from matings of these "double heterozygotes," 6 were confirmed by Southern blot analysis and PCR to be homozygous null for both mdmx and p53 (Fig. 5ACitation and Table 1Citation ). Northern blot hybridization was used to demonstrate the loss of mdmx expression in the viable p53 null/mdmx null animals (Fig. 5B)Citation . The rescue of the mdmx1/mdmx1 embryonic lethality in the absence of p53 constitutes strong genetic evidence that mdmx is, in fact, a potent negative regulator of p53 function and confirms the results of an important recent report by Parant et al. (20) . The double-null animals appeared normal but were susceptible to early tumor development, similar to p53 null animals (21) . The five p53/mdmx double null animals that were monitored for tumor development died of lymphoid tumors with a mean life span of 26 weeks.



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  		Fig. 5. A, mdmx genotypic analysis of offspring of mdmx/p53 double heterozygote matings. B, mdmx Northern blot analyses of total RNA from selected tissues (that normally express high levels of mdmx RNA) from p53 null, mdmx wild-type; p53 null, mdmx1/+; and p53 null, mdmx1/mdmx1 animals. Arrows, mdmx transcripts. This probe recognizes the ~1.3 kb fusion transcript containing the selectable neomycin phosphotransferase marker resulting from the trapping vector insertion as well as endogenous mdmx transcripts. The ethidium bromide-stained gels show approximately equal loading.

 

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  		Table 1 Genotypic analyses of offspring resulting from mdmx, p53 double heterozygote matings

Numbers represent offspring derived from 14 litters from seven separate crosses. Ninety-nine total offspring were analyzed. Observed (expected).

 
Interestingly, the mdmx1/mdmx1 embryos studied in the present report died on E10–E12, whereas the time of death of homozygous mutant mdmx embryos reported previously by Parant et al. (20) was E7.5-E8.5. This discrepancy may be attributable to subtle differences in genetic background of the animals and ES cells used to generate the mutant mice.

Previous in vitro transient overexpression studies have shown that increased Mdmx inhibits Mdm2-mediated degradation of p53, leading to enhanced p53 levels (10 , 11) . In contrast, our study shows that reduction of mdmx in genetically altered primary fibroblast cell lines leads to increased p53 levels. Our observation of an increased p53 level concomitant with mdmx reduction is consistent with the reduced growth and increased apoptosis of mdmx1/+ fibroblasts as well as with the finding that loss of p53 rescues the lethality of mdmx-null mice. An understanding of the mechanistic basis for these apparent contradictions may shed new light on the complex nature of p53 regulation.

The lethality of mdm2 (8 , 9) and mdmx null mice shows clearly that these proteins cannot compensate for each other, suggesting that both are required to control the p53 pathway. p53 is an important tumor suppressor gene product, and the correlation between loss of functional p53 and tumor formation in animals and humans is well established. Because mdmx functions as a negative regulator of the p53 pathway, it may also be involved in tumorigenesis. This notion is supported by the report of amplification and overexpression of the MDMX gene in a subset of malignant human gliomas containing no p53 mutations (22) , suggesting that excess MDMX may contribute to tumor development by blocking p53 function. Our results suggest that MDMX, similar to MDM2, offers a potential target for antitumor therapies for the roughly 50% of human cancers that retain wild-type p53.


   ACKNOWLEDGMENTS
 
We thank C. Thomas Caskey and the Merck Genome Institute for selections from OmniBank, and we thank Michelle Campbell for generating the flanking probe used for mdmx Southern blotting.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Lexicon Genetics, Incorporated, 4000 Research Forest Drive, The Woodlands, TX 77381. Phone: (281) 863-3074; Fax: (281) 863-8088; E-mail: nzhang{at}lexgen.com Back

2 The abbreviation used is: ES, embryonic stem. Back

Received 11/20/01. Accepted 3/26/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 

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