Terzian Tamara, Wang Yongxing, Van Pelt Carolyn S, Box Neil F, Travis Elisabeth L, Lozano Guillermina
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.
Mol Cell Biol. 2007 Aug;27(15):5479-85. doi: 10.1128/MCB.00555-06. Epub 2007 May 25.
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.
肿瘤抑制因子p53可通过多种机制失活，这些机制包括p53基因本身的突变以及p53抑制剂MDM2和MDM4水平的升高。缺乏Mdm2或Mdm4的小鼠表现出胚胎致死表型，而同时缺失p53可完全挽救该表型。在此我们表明，Mdm2和Mdm4单倍体不足会导致p53活性增加，表现为对DNA损伤的敏感性增加和转化潜能降低。此外，在体内肿瘤发生过程中，与Emu-myc小鼠相比，Emu-myc Mdm4+/-小鼠的B细胞淋巴瘤发病延迟。另外，Mdm2+/- Mdm4+/-双杂合小鼠无法存活，并在造血和小脑发育方面表现出缺陷。通过缺失单个p53等位基因可纠正Mdm2+/- Mdm4+/-小鼠的缺陷。这些发现突出了p53对MDM2和MDM4水平的高度敏感性，并表明某些细胞类型可能对抑制Mdm-p53相互作用的治疗药物更为敏感。
