International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


POSTER 134 - GENETIC INTERACTIONS BETWEEN MDMX, MDM2, P53, AND A DOMINANT NEGATIVE P53 R172H

JM Parant
MD Anderson Cancer Center

Chavez-Reyes A, Lang G, Lozano G.
MD Anderson Cancer Center

MDM2 is a p53 transcriptional target, that binds to p53 and inhibiting it's activity. Mice carrying a homozygous null allele for mdm2 exhibit an early embryonic lethality at 5.5 dpc due to increased apoptosis. MDMX, a homolog of MDM2, can also bind p53 and inhibit it. Mdmx homozygous null mice are early embryonic lethal due to a lack of proliferation beyond 7.5 dpc. Surprisingly both mdm2 and mdmx homozygous null mice are viable in a p53 null background.  These data further define the p53 pathway, in which MDMX inhibits p53 dependent cell cycle arrest and MDM2 inhibits p53 dependent apoptosis. To determine if MDM2 and MDMX were compensating for each other in p53-independent functions, we attempted to generate mdm2/mdmx/p53 triple null mice.  Surprisingly, the triple null mice are viable and fertile, indicating no compensatory developmental function. However preliminary data suggest that the survival curve of the triple null mice is severely reduced compared to mdm2/p53 double null, mdmx/p53 double null or p53 null mice. Thus MDMX and MDM2 may have redundant p53 independent roles.Additionally we have generated mice carrying a p53 mutation R172H analogous to the Li-Fraumeni dominant negative hotspot mutation R175H. We have tested this mutant for dominant negative activity by attempting to generate mdm2-/- p53 R172H/+ and mdmx -/- p53R172H/+ mice. Although a complete rescue was not obtained both mdm2 -/- and mdmx -/- are partially rescued in a p53 R172H/+ background. Indicating that the R172H allele acts as a weak dominant negative in vivo.


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