Tashakori Mehrnoosh, Zhang Yun, Xiong Shunbin, You M James, Lozano Guillermina
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas Graduate School of Biomedical Sciences, Program in Genes and Development.
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Mol Cancer Res. 2016 Jan;14(1):56-65. doi: 10.1158/1541-7786.MCR-15-0346. Epub 2015 Nov 2.
Mdm4 negatively regulates the p53 tumor suppressor. Mdm4 loss in mice leads to an embryonic lethal phenotype that is p53-dependent. Biochemical studies indicate that Mdm4 also binds p73, a member of the p53 family, with higher affinity than p53. In this study, the significance of the Mdm4 and p73 interaction in vivo during embryogenesis and tumorigenesis was examined. The data revealed that p73 loss did not rescue either the early Mdm4-deficient embryonic lethality or the runted phenotype of Mdm4(Δ2/Δ2) p53(+/-) embryos. Furthermore, studies in the developing central nervous system wherein both genes have prominent roles indicated that loss of p73 also did not rescue the Mdm4-null brain phenotype as did p53 loss. This p53 dependency occurred despite evidence for p73-specific transcriptional activity. In tumor studies, the combination of Mdm4 overexpression and p73 loss did not alter survival of mice or the tumor spectrum as compared with Mdm4 overexpression alone. In summary, these data demonstrate that the Mdm4-p73 axis cannot override the dominant role of p53 in development and tumorigenesis.
Genetic characterization of the Mdm4 and p73 interaction during development and tumorigenesis suggests new insight into the role of p53 family members, which may influence treatment options for patients.
Mdm4对p53肿瘤抑制因子起负调控作用。小鼠中Mdm4缺失会导致一种依赖p53的胚胎致死表型。生化研究表明，Mdm4还能与p53家族成员p73结合，且亲和力高于p53。在本研究中，我们检测了胚胎发育和肿瘤发生过程中Mdm4与p73相互作用在体内的重要性。数据显示，p73缺失并不能挽救早期Mdm4缺陷型胚胎致死率，也不能挽救Mdm4(Δ2/Δ2)p53(+/-)胚胎的发育迟缓表型。此外，在中枢神经系统发育过程中，这两个基因都发挥着重要作用，研究表明，与p53缺失不同，p73缺失也不能挽救Mdm4基因敲除后的脑表型。尽管有证据表明p73具有特异性转录活性，但这种p53依赖性仍然存在。在肿瘤研究中，与单独过表达Mdm4相比，Mdm4过表达与p73缺失的联合作用并未改变小鼠的存活率或肿瘤谱。总之，这些数据表明，Mdm4-p73轴无法超越p53在发育和肿瘤发生中的主导作用。
对发育和肿瘤发生过程中Mdm4与p73相互作用的基因特征分析，为深入了解p53家族成员的作用提供了新的视角，这可能会影响患者的治疗选择。
