Calabrò Viola, Mansueto Gelsomina, Parisi Tiziana, Vivo Maria, Calogero Raffaele A, La Mantia Girolama
Department of Genetics and General and Molecular Biology, University of Naples "Federico II," via Mezzocannone 8, 80134 Napoli, Italy.
J Biol Chem. 2002 Jan 25;277(4):2674-81. doi: 10.1074/jbc.M107173200. Epub 2001 Nov 19.
Genetic alteration of the p53 tumor suppressor gene, which monitors DNA damage and operates cell cycle checkpoints, is a major factor in the development of human malignancies. The p53 protein belongs to a family that also includes two structurally related proteins, p63 and p73. Although all three proteins share similar transcriptional functions and antiproliferative effects, each of them appears to play a distinct role in development and tumor suppression. One of the principal regulators of p53 activity is the MDM2 protein. The interaction of MDM2 with p53 inhibits p53 transcriptional activity and targets p53 for ubiquitin-dependent degradation. The ability of MDM2 to inhibit p53 functions is antagonized by the ARF oncosuppressor protein. We show here that like p53, the p63alpha and p63gamma isoforms are able to associate with human MDM2 (HDM2). Overexpression of HDM2 increased the steady-state level of intracellular p63 and enhanced its transcriptional activity. Both effects appeared to be counteracted by ARF coexpression. These data indicate that p63 can be activated by HDM2 under conditions in which p53 is inhibited. Therefore, HDM2 expression could support p63-specific transcriptional functions on a common set of genes, keeping interference by p53 at a minimum.
p53肿瘤抑制基因可监测DNA损伤并调控细胞周期检查点，该基因的遗传改变是人类恶性肿瘤发生的主要因素。p53蛋白属于一个家族，该家族还包括另外两种结构相关的蛋白，即p63和p73。尽管这三种蛋白都具有相似的转录功能和抗增殖作用，但它们在发育和肿瘤抑制过程中似乎发挥着不同的作用。p53活性的主要调节因子之一是MDM2蛋白。MDM2与p53的相互作用会抑制p53的转录活性，并将p53靶向泛素依赖性降解。ARF抑癌蛋白可拮抗MDM2抑制p53功能的能力。我们在此表明，与p53一样，p63α和p63γ亚型能够与人MDM2（HDM2）结合。HDM2的过表达增加了细胞内p63的稳态水平，并增强了其转录活性。这两种效应似乎都被ARF的共表达所抵消。这些数据表明，在p53受到抑制的条件下，p63可被HDM2激活。因此，HDM2的表达可以支持p63对一组共同基因的特异性转录功能，同时将p53的干扰降至最低。
