El-Dahr Samir, Hilliard Sylvia, Saifudeen Zubaida
Department of Pediatrics, Section of Pediatric Nephrology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
J Mol Cell Biol. 2017 Feb 1;9(1):26-33. doi: 10.1093/jmcb/mjx005.
While p53 activity is required for tumour suppression, unconstrained p53 activity on the other hand is detrimental to the organism, resulting in inappropriate cellular death or proliferation defects. Unimpeded p53 activity is lethal in the developing embryo, underlining the need for maintaining a tight control on p53 activity during this period. The critical role of the negative regulators of p53, Mdm2 and Mdm4, in vertebrate development came to light by fatal disruption of embryogenesis that was observed with Mdm2 and Mdm4 gene deletions in mice. Embryonic lethality was rescued only by superimposing p53 removal. Here we summarize the contribution of the Mdm2/Mdm4-p53 axis that occurs at multiple steps of kidney development. Conditional, cell type-specific deletions reveal distinct functions of these proteins in renal morphogenesis. The severe impact on the renal phenotype from targeted gene deletions underscores the critical role played by the Mdm2/Mdm4-p53 nexus on nephrogenesis, and emphasizes the need to monitor patients with aberrations in this pathway for kidney function defects and associated cardiovascular dysfunction.
虽然p53活性对于肿瘤抑制是必需的，但另一方面，不受限制的p53活性对生物体是有害的，会导致不适当的细胞死亡或增殖缺陷。不受阻碍的p53活性在发育中的胚胎中是致命的，这凸显了在此期间对p53活性进行严格控制的必要性。p53的负调节因子Mdm2和Mdm4在脊椎动物发育中的关键作用，是通过观察到小鼠中Mdm2和Mdm4基因缺失导致胚胎发育的致命破坏而发现的。只有通过叠加p53缺失才能挽救胚胎致死性。在这里，我们总结了Mdm2/Mdm4-p53轴在肾脏发育多个步骤中的作用。条件性、细胞类型特异性缺失揭示了这些蛋白在肾脏形态发生中的不同功能。靶向基因缺失对肾脏表型的严重影响强调了Mdm2/Mdm4-p53关系在肾发生中的关键作用，并强调需要监测该途径存在异常的患者是否存在肾功能缺陷及相关的心血管功能障碍。
