De Laurenzi V, Melino G
IDI-IRCCS Biochemistry Lab., c/o Department of Experimental Medicine and Biochemical Sciences, University Tor Vergata, Rome, Italy.
Ann N Y Acad Sci. 2000;926:90-100. doi: 10.1111/j.1749-6632.2000.tb05602.x.
Even though the tumor suppressor gene p53 is highly important in human cancer, as indicated by the fact that it is mutated in about 50% of cases, up to a few years ago no similar proteins had been identified. Recently, two p53 homologues have been identified, p73 and p63, with high amino acid identity suggesting similar functions. Indeed, like p53, p73 as well (i) can bind mdmX, mdm2, p300/CAF and adenovirus E4-orf6 proteins, (ii) can trigger several promoters including p21, bax, mdm2, gadd45, cyclin G, IGFBP3, 14-3-3 sigma, (iii) is able to trigger cell death, (iv) is involved in the DNA damage response, although through a different pathway. Here we analyze the data present in the literature in search of diverging pathways among the p53, p63, p73 family. Both p63 and p73 present two significant structural peculiarities: the presence of an extended non-conserved C-terminus containing a sterile alpha motive (SAM), typical of developmental proteins, and the presence of number of different splicing isoforms differing in the N-terminus or in the absence of the transactivation domain (delta N forms), acting as dominant negative. The mouse knockout of p63 and p73, unlike the ones for p53, shows developmental abnormalities; p63 and p73 are rarely mutated in human cancers; both genes are regulated in different differentiation models. This strongly suggests the involvement of p63 and p73 in development. A picture is emerging showing a gradient of function among p53, p73, p63 ranging from tumor suppression to development.
尽管肿瘤抑制基因p53在人类癌症中非常重要，约50%的病例中该基因会发生突变，但直到几年前，尚未发现类似的蛋白质。最近，已鉴定出两种p53同源物，即p73和p63，它们具有高度的氨基酸同源性，提示功能相似。实际上，与p53一样，p73也（i）能够结合mdmX、mdm2、p300/CAF和腺病毒E4-orf6蛋白，（ii）能够激活包括p21、bax、mdm2、gadd45、细胞周期蛋白G、IGFBP3、14-3-3 sigma在内的多个启动子，（iii）能够引发细胞死亡，（iv）参与DNA损伤反应，尽管其途径与p53不同。在此，我们分析文献中的数据，以寻找p53、p63、p73家族中不同的信号通路。p63和p73都有两个显著的结构特点：存在一个延伸的非保守C末端，其中包含一个无活性α基序（SAM），这是发育蛋白所特有的；存在多个不同的剪接异构体，它们在N末端或缺乏反式激活结构域（δN形式）方面存在差异，可作为显性负性蛋白发挥作用。与p53基因敲除的小鼠不同，p63和p73基因敲除的小鼠表现出发育异常；p63和p73在人类癌症中很少发生突变；这两个基因在不同的分化模型中受到调控。这强烈提示p63和p73参与了发育过程。一幅图景正在浮现，显示p53、p73、p63之间存在从肿瘤抑制到发育的功能梯度。
