Haploinsufficiency of Mdm2 and Mdm4 in tumorigenesis and development.
The tumor suppressor p53 is inactivated by multiple mechanisms that include mutations of the p53 gene itself and increased levels of the p53 inhibitors MDM2 and MDM4. Mice lacking Mdm2 or Mdm4 exhibit embryo-lethal phenotypes that are completely rescued by concomitant deletion of p53. Here we show that Mdm2 and Mdm4 haploinsufficiency leads to increased p53 activity, exhibited as increased sensitivity to DNA damage and decreased transformation potential. Moreover, in in vivo tumor development, Emu-myc Mdm4+/- mice show a delayed onset of B-cell lymphomas compared to Emu-myc mice. Additionally, Mdm2+/- Mdm4+/- double-heterozygous mice are not viable and exhibit defects in hematopoiesis and cerebellar development. The defects in Mdm2+/- Mdm4+/- mice are corrected by deletion of a single p53 allele. These findings highlight the exquisite sensitivity of p53 to Mdm2 and Mdm4 levels and suggest that some cell types may be more sensitive to therapeutic drugs that inhibit the Mdm-p53 interaction.
Terzian
Tamara
T
Department of Cancer Genetics, Box 1010, The University of Texas M. D. Anderson Cancer Center, Baylor College of Medicine, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Wang
Yongxing
Y
Van Pelt
Carolyn S
CS
Box
Neil F
NF
Travis
Elisabeth L
EL
Lozano
Guillermina
G
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001853:Bone Marrow / Q000002:abnormalities; D002471:Cell Transformation, Neoplastic; D002531:Cerebellum / Q000002:abnormalities; D004622:Embryo, Mammalian / Q000002:abnormalities; D006238:Haploidy; D006410:Hematopoiesis; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D011836:Radiation Tolerance; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases