Tumor formation and inactivation of RIZ1, an Rb-binding member of a nuclear protein-methyltransferase superfamily
Tumor formation and inactivation of RIZ1, an Rb-binding member of a nuclear protein-methyltransferase superfamily
复制标题
DOI：
10.1101/gad.870101
复制
发表时间：
2001-09-01
影响因子：
10.5
通讯作者：
Huang, S
中科院分区：
文献类型：
--
作者：
Steele-Perkins, G;Fang, W;Huang, S
视网膜母细胞瘤蛋白相互作用锌指基因RIZ （PRDM2）是参与染色质介导基因表达的核蛋白-甲基转移酶（MTase）超家族的成员。该基因产生两种蛋白产物，RIZ1含有保守的MTase结构域，而RIZ2缺乏该结构域。RIZ1基因的表达在人类癌症中经常沉默，并且该基因也是微卫星不稳定癌症中移码突变的常见靶标。我们现在报道了在小鼠中有RIZ1位点靶向突变的研究。这种突变使RIZ1失活，但不会使RIZ2失活。这些RIZ1突变小鼠是可存活和可生育的，但表现出弥漫性大b细胞淋巴瘤（DLBL）的高发病率和广谱的不寻常肿瘤。RIZ1缺失也会加速p53杂合突变小鼠的肿瘤发生。最后，在人类肿瘤组织和细胞系中发现了几种RIZ1错义突变；其中一种在人类DLBL肿瘤中尤为常见。这些错义突变，以及先前描述的移码突变，都映射到MTase功能域。所有这些都破坏了RIZ1增强雌激素受体转录激活的能力。这些数据表明肿瘤形成与RIZ1的MTase结构域之间存在直接联系，并首次在甲基转移酶中描述了肿瘤易感基因。
The retinoblastoma protein-interacting zinc finger gene RIZ (PRDM2) is a member, by sequence homology, of a nuclear protein-methyltransferase (MTase) superfamily involved in chromatin-mediated gene expression. The gene produces two protein products, RIZ1 that contains a conserved MTase domain and RIZ2 that lacks the domain. RIZ1 gene expression is frequently silenced in human cancers, and the gene is also a common target of frameshift mutation in microsatellite-unstable cancers. We now report studies of mice with a targeted mutation in the RIZ1 locus. The mutation inactivates RIZ1 but not RIZ2. These RIZ1 mutant mice were viable and fertile but showed a high incidence of diffuse large B-cell lymphomas (DLBL) and a broad spectrum of unusual tumors. RIZ1 deficiency also accelerated tumorigenesis in p53 heterozygous mutant mice. Finally, several missense mutations of RIZ1 were found in human tumor tissues and cell lines; one of these was particularly common in human DLBL tumors. These missense mutations, as well as the previously described frameshift mutation, all mapped to the MTase functional domains. All abolished the capacity of RIZ1 to enhance estrogen receptor activation of transcription. These data suggest a direct link between tumor formation and the MTase domain of RIZ1 and describe for the first time a tumor susceptibility gene among methyltransferases.