Functional identification of LZTS1 as a candidate prostate tumor suppressor gene on human chromosome 8p22
Functional identification of LZTS1 as a candidate prostate tumor suppressor gene on human chromosome 8p22
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DOI：
10.1038/sj.onc.1204539
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发表时间：
2001-07-12
期刊：
影响因子：
8
通讯作者：
Chinault, AC
中科院分区：
文献类型：
--
作者：
Cabeza-Arvelaiz, Y;Sepulveda, JL;Chinault, AC
人类基因组 8p21-22 区域的缺失是前列腺癌中最常见的遗传改变之一。对不同肿瘤组织（包括前列腺）的多项研究表明，该区域可能存在多种肿瘤抑制基因（TSG）。为了鉴定 8p22 上的候选 TSG，组装了跨越该区域的 YAC 重叠群，并将用选择标记 (neo) 改造的 YAC 克隆转移到大鼠前列腺 AT6,2 细胞中，两个重叠的 YAC 克隆显示出大大降低的集落形成效率，表明它们可能携带 TSG。包含重叠区域的两个 BAC 克隆似乎也对 AT6,2 细胞的生长发挥抑制作用。数据库搜索映射到关键区域的基因，识别出一个称为FEZ1 (LZTS1) 作为潜在的候选抑制基因。随后的实验表明，LZTS1 cDNA 的过表达抑制了 AT6,2、HEK-293 和 LNCaP 细胞的稳定集落形成效率。相反，LZTS1 转染的 Rat-1 和 RM1 细胞生长受到刺激。数据库搜索还发现了 LZTS1 mRNA 的其他亚型，以及让人想起转录因子中发现的 LZTS1 蛋白结构域。这些数据共同表明，LZTS1 基因参与细胞生长的调节，其功能丧失可能导致前列腺癌以及其他癌症的发生。
Deletions in the 8p21-22 region of the human genome are among the most common genetic alterations in prostate carcinomas. Several studies in different tumor tissues, including prostate, indicate that there are probably multiple tumor suppressor genes (TSGs) present in this region. To identify candidate TSGs on 8p22 a YAC contig spanning this region was assembled and YAC clones retrofitted with a selectable marker (neo) were transferred into rat prostate AT6,2 cells, Two overlapping YAC clones showed greatly reduced colony-forming efficiency, indicating they may carry a TSG, Two BAC clones encompassing the overlapping region also appeared to exert suppressive effects on the growth of AT6,2 cells, Database searches for genes mapped to the critical region identified a gene known as FEZ1 (LZTS1) as a potential candidate suppressor gene. Subsequent experiments showed that over-expression of LZTS1 cDNA inhibited stable colony-forming efficiencies of AT6,2, HEK-293 and LNCaP cells. In contrast, LZTS1-transfected Rat-1 and RM1 cells were growth-stimulated. Database searches also identified additional isoforms of the LZTS1 mRNA, as well as LZTS1 protein domains reminiscent of those found in transcription factors. Together these data suggest that the LZTS1 gene is involved in the regulation of cell growth and its loss of function may contribute to the development of prostatic carcinomas, as well as other cancers.