Loss of one but not twomdm2 null alleles alters the tumour spectrum inp53 null mice

Abstract

The transcriptional activity of the p53 tumour suppressor is inhibited by binding to MDM2. The in vivo significance of this interaction was established in mdm2 null mice. Embryonic lethality due to loss of mdm2 is completely rescued by deletion of p53, indicating that the lethality is due to inability to down‐modulate p53 function. The production of mice null for both p53 and mdm2 led to an assessment of the role of MDM2 in tumour development. Tumour latency and spectrum in p53 null mice were monitored in the presence or absence of mdm2. Two unusual findings resulted: tumour latency in p53 null/mdm2 heterozygous mice was longer than in p53/mdm2 double‐null mice; and the incidence of sarcomas was higher in p53 null/mdm2 heterozygous mice than in p53 null or p53/mdm2 double‐null mice. These data raise the possibility that heterozygosity at the mdm2 locus in the absence of p53 affects the development of tumours of mesenchymal origin. Copyright © 1999 John Wiley & Sons, Ltd.

Decreased Mdm2 expression inhibits tumor development induced by loss of ARF

“…Consistent with this idea, Mdm2 þ /À p53 À/À mice had an altered tumor spectrum and a slightly longer survival as compared to Mdm2 þ / þ p53 À/À mice (McDonnell et al, 1999). We observed that loss of one allele of Mdm2 in ARF-null mice profoundly extended survival, but did not appear to grossly alter the tumor spectrum.…”

The Mdm2–p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor

“…Intriguingly, tumor latency was shorter in Mdm2/p53 doubleknockout mice as compared with p53-null mice that are heterozygous for the Mdm2 deletion. In addition, homozygous deletion of Mdm2 led to a change in tumor spectrum with an increased incidence of sarcomas (McDonnell et al 1999). Taken together, such findings support a role for Mdm2 in tumorigenesis that is independent of its effects on p53.…”

Mdm2-mediated ubiquitylation: p53 and beyond

“…In fact, p53-Mdm2 double null mice have indistinguishable survival curves and tumor spectra as p53-null mice further underscoring the importance of the p53-Mdm2 relationship. 26 Cell type and tissue specificity of the p53-Mdm2 interaction was subsequently examined using conditional alleles of Mdm2. 27 Loss of Mdm2 in neuronal and erythroid progenitor cells, post-mitotic neurons, smooth muscle cells and in the heart bring about cell death which is rescued by deletion of p53.…”

“…There has been a great deal of skepticism regarding the p53-independent functions of Mdm2, mainly because p53-Mdm2 double knock out (KO) (DKO) mice are indistinguishable from p53 KO mice. 26 Some of these interactions may only become effective and relevant under conditions in which Mdm2 levels are elevated, such as under stress -in response to activation of the negative feedback loop -and in human tumors. As mentioned above Mdm2 expression is dramatically elevated in some tumors; under these conditions, a pool of Mdm2 may become available to target numerous other substrates, including proteins that are not directly involved in the p53 pathway.…”