Clarke A R
Department of Pathology, University of Edinburgh, UK.
Cancer Metastasis Rev. 1995 Jun;14(2):125-48. doi: 10.1007/BF00665796.
Loss of function of one or both of the two tumour suppressor genes p53 and RB-1 has been recognised as an important step in the development of a variety of human neoplasias for some time. By virtue of the ability to manipulate the genome of murine embryonic stem cells in culture, it has become possible to generate strains of mice which bear inactivations of the murine counterparts of these genes. This article attempts to bring together some of the many results obtained from these murine strains which are shedding light both on the normal role played by both of these genes and the consequences of their dysfunction. Surprisingly neither gene product is revealed to have an indispensable role at the level of the single cell. Hence, even though the Rb-1 gene product clearly has an important role in cell cycle regulation animals constitutively deficient in this gene develop relatively normally for the first 10 days of embryogenesis. It is only at and beyond this stage of development that a requirement for Rb-1 becomes clear, in the regulation of certain cell populations through control of both proliferation and apoptosis. That loss of function of Rb-1 is associated with tumorigenesis is confirmed by the development of tumours of the pituitary gland within heterozygotes. The retinas of these animals, the target organ for tumorigenesis in human RB-1 heterozygotes, remain unaffected. The majority of mice homozygous for an inactivating p53 mutation survive to birth, but then rapidly succumb to tumorigenesis. Heterozygotes also develop tumours, but with a delayed time course and altered spectrum. Analysis of several tissue types from the mutant animals has shown p53 to be crucial for the normal induction of apoptosis following DNA damage, and it is thought that failure of this process is a key predisposing step towards tumorigenesis within the mutant animals. Finally, studies on these and other transgenic strains have revealed interactions between pathways governed by these two genes. For example, the fate of Rb-1 deficient cells has been shown, in some tissues at least, to be dependent upon the functional status of p53.
一段时间以来，肿瘤抑制基因p53和RB - 1中一个或两个功能的丧失被认为是多种人类肿瘤发生发展的重要步骤。凭借在培养中操纵小鼠胚胎干细胞基因组的能力，现已能够培育出携带这些基因小鼠对应基因失活的小鼠品系。本文试图汇总从这些小鼠品系中获得的众多结果，这些结果有助于阐明这两个基因的正常作用及其功能障碍的后果。令人惊讶的是，在单细胞水平上，这两种基因产物均未显示出不可或缺的作用。因此，尽管Rb - 1基因产物在细胞周期调控中显然具有重要作用，但在胚胎发育的前10天，该基因持续缺陷的动物发育相对正常。只有在这个发育阶段及之后，通过控制增殖和凋亡来调节某些细胞群时，对Rb - 1的需求才变得明显。杂合子中垂体肿瘤的发生证实了Rb - 1功能丧失与肿瘤发生有关。这些动物的视网膜，即人类RB - 1杂合子肿瘤发生的靶器官，未受影响。大多数p53失活突变纯合的小鼠能存活至出生，但随后迅速死于肿瘤发生。杂合子也会发生肿瘤，但发病时间延迟且肿瘤谱改变。对突变动物几种组织类型的分析表明，p53对于DNA损伤后正常诱导细胞凋亡至关重要，并且认为这一过程的失败是突变动物肿瘤发生的关键易感步骤。最后，对这些及其他转基因品系的研究揭示了这两个基因所调控途径之间的相互作用。例如，至少在某些组织中，已表明Rb - 1缺陷细胞的命运取决于p53的功能状态。
