Rufini Alessandro, Agostini Massimiliano, Grespi Francesca, Tomasini Richard, Sayan Berna S, Niklison-Chirou Maria Victoria, Conforti Franco, Velletri Tania, Mastino Antonio, Mak Tak W, Melino Gerry, Knight Richard A
Toxicology Unit, Medical Research Council, Leicester, LE1 9HN, United Kingdom.
Genes Cancer. 2011 Apr;2(4):491-502. doi: 10.1177/1947601911408890.
p73 is a tumor suppressor belonging to the p53 family of transcription factors. Distinct isoforms are transcribed from the p73 locus. The use of 2 promoters at the N-terminus allows the expression of an isoform containing (TAp73) or not containing (ΔNp73) a complete N-terminal transactivation domain, with the latter isoform capable of a dominant negative effect over the former. In addition, both N-terminal variants are alternatively spliced at the C-terminus. TAp73 is a bona fide tumor suppressor, being able to induce cell death and cell cycle arrest; conversely, ΔNp73 shows oncogenic properties, inhibiting TAp73 and p53 functions. Here, we discuss the latest findings linking p73 to cancer. The generation of isoform specific null mice has helped in dissecting the contribution of TA versus ΔNp73 isoforms to tumorigenesis. The activity of both isoforms is regulated transcriptionally and by posttranslational modification. p73 dysfunction, particularly of TAp73, has been associated with mitotic abnormalities, which may lead to polyploidy and aneuploidy and thus contribute to tumorigenesis. Although p73 is only rarely mutated in cancer, the tumor suppressor actions of TAp73 are inhibited by mutant p53, a finding that has important implications for cancer therapy. Finally, we discuss the expression and role of p73 isoforms in human cancer, with a particular emphasis on the neuroblastoma cancer model. Broadly, the data support the hypothesis that the ratio between TAp73 and ΔNp73 is crucial for tumor progression and therapeutic response.
p73是一种肿瘤抑制因子，属于转录因子p53家族。从p73基因座转录出不同的异构体。在N端使用两个启动子可表达含有（TAp73）或不含有（ΔNp73）完整N端反式激活结构域的异构体，后一种异构体对前一种异构体具有显性负效应。此外，两种N端变体在C端也存在可变剪接。TAp73是一种真正的肿瘤抑制因子，能够诱导细胞死亡和细胞周期停滞；相反，ΔNp73具有致癌特性，可抑制TAp73和p53的功能。在此，我们讨论将p73与癌症联系起来的最新研究结果。异构体特异性敲除小鼠的产生有助于剖析TA与ΔNp73异构体对肿瘤发生的贡献。两种异构体的活性都受到转录调控和翻译后修饰的调节。p73功能障碍，尤其是TAp73的功能障碍，与有丝分裂异常有关，这可能导致多倍体和非整倍体，从而促进肿瘤发生。尽管p73在癌症中很少发生突变，但TAp73的肿瘤抑制作用会被突变型p53抑制，这一发现对癌症治疗具有重要意义。最后，我们讨论p73异构体在人类癌症中的表达和作用，特别强调神经母细胞瘤癌症模型。总体而言，数据支持这样一种假设，即TAp73和ΔNp73之间的比例对肿瘤进展和治疗反应至关重要。
