Full p53 transcriptional activation potential is dispensable for tumor suppression in diverse lineages
Full p53 transcriptional activation potential is dispensable for tumor suppression in diverse lineages
复制标题
DOI：
10.1073/pnas.1111245108
复制
发表时间：
2011-10-11
影响因子：
11.1
通讯作者：
Attardi, Laura D.
中科院分区：
文献类型：
--
作者：
Jiang, Dadi;Brady, Colleen A.;Attardi, Laura D.
超过一半的人类癌症，在各种各样的类型中，保持着p53肿瘤抑制基因的突变。虽然P53通过诱导细胞凋亡或细胞周期停滞来限制肿瘤的发生，但其抑制肿瘤的分子机制一直难以捉摸。P53在体外最具特征的活性是作为转录激活剂，但在体外对大量额外的P53生化活性的鉴定使人们不清楚是什么机制导致了肿瘤抑制。在这里，我们使用表达转录激活妥协的p53突变的小鼠品系p53(25，26)，在几个组织中评估转录激活对p53肿瘤抑制功能的重要性。P53(25，26)由于许多经典的P53靶基因的反式激活而严重受损，包括p21，NOXA和PUMA，但它保留激活包括Bax在内的一小部分P53靶基因的能力。令人惊讶的是，p53(25，26)仍然可以抑制来源于上皮、间充质、中枢神经系统和淋巴系的癌症的肿瘤生长。因此，在一系列组织类型中，大多数P53靶基因的完全反式激活对于P53的肿瘤抑制功能是必不可少的。相比之下，转录激活突变体P53(25，26，53，54)是完全缺陷的反式激活，无法抑制肿瘤的发展。这些发现表明，转录激活确实对p53抑癌功能具有广泛的关键作用，尽管这一要求反映了p53(25，26)的转录活性有限，而不是对全部p53靶基因的强烈反式激活。
Over half of all human cancers, of a wide variety of types, sustain mutations in the p53 tumor suppressor gene. Although p53 limits tumorigenesis through the induction of apoptosis or cell cycle arrest, its molecular mechanism of action in tumor suppression has been elusive. The best-characterized p53 activity in vitro is as a transcriptional activator, but the identification of numerous additional p53 biochemical activities in vitro has made it unclear which mechanism accounts for tumor suppression. Here, we assess the importance of transcriptional activation for p53 tumor suppression function in vivo in several tissues, using a knock-in mouse strain expressing a p53 mutant compromised for transcriptional activation, p53(25,26). p53(25,26) is severely impaired for the transactivation of numerous classical p53 target genes, including p21, Noxa, and Puma, but it retains the ability to activate a small subset of p53 target genes, including Bax. Surprisingly, p53(25,26) can nonetheless suppress tumor growth in cancers derived from the epithelial, mesenchymal, central nervous system, and lymphoid lineages. Therefore, full transactivation of most p53 target genes is dispensable for p53 tumor suppressor function in a range of tissue types. In contrast, a transcriptional activation mutant that is completely defective for transactivation, p53(25,26,53,54), fails to suppress tumor development. These findings demonstrate that transcriptional activation is indeed broadly critical for p53 tumor suppressor function, although this requirement reflects the limited transcriptional activity observed with p53(25,26) rather than robust transactivation of a full complement of p53 target genes.