High frequency in esophageal cancers of p53 alterations inactivating the regulation of genes involved in cell cycle and apoptosis
High frequency in esophageal cancers of p53 alterations inactivating the regulation of genes involved in cell cycle and apoptosis
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DOI：
10.1093/carcin/21.4.563
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发表时间：
2000-04-01
期刊：
影响因子：
4.7
通讯作者：
Frebourg, T
中科院分区：
文献类型：
--
作者：
Robert, V;Michel, P;Frebourg, T
食管癌中经常检测到抑癌基因 p53 的体细胞突变，但其生物学意义仍有待确定。 p53 的肿瘤抑制活性部分源于其反式激活参与细胞周期和细胞凋亡的基因（例如 p21、bax 和 PIG3）的能力，并且一些 p53 突变可能对这些靶基因的反式激活产生不同的影响。我们开发了酵母菌株，其中野生型 p53 报告质粒（含有这些靶基因中存在的 p53 结合位点）的激活会引起菌落颜色的变化（红色/白色）。使用这些菌株，我们分析了居住在法国诺曼底这一高发地理区域的 56 例食管癌患者，其中 47 例肿瘤 (84%) 被标记为 p21、bax 和 PIG3 报告菌株突变，在大多数病例 (76%) 中，红色菌落的百分比表明两个 p53 等位基因均失活。测序分析允许在每个阳性样本中鉴定出 p53 突变，并且突变谱与烟草和酒精的病因作用一致。这些结果证实了食管癌中双等位基因p53突变的高频率，并强烈表明其生物学后果是参与细胞周期和细胞凋亡的基因反式激活的完全改变，这表明p53改变是食管癌发生的关键事件。
Somatic mutations of the tumor suppressor gene p53 have been frequently detected in esophagal cancers, but their biological significance remains to be established. The tumor suppressor activity of p53 results in part from its ability to transactivate genes involved in the cell cycle and apoptosis, such as p21, bax and PIG3, and some p53 mutations may have a differential effect on the transactivation of these target genes. We developed yeast strains in which the activation by wild-type p53 of reporter plasmids containing p53 binding sites present within these target genes induces a change in the color of the colonies (red/ white). Using these strains, we analyzed 56 esophageal cancers from patients residing in Normandy, France, a high incidence geographic area, Forty-seven tumors (84%), scored as mutant with the p21, bax and PIG3 reporter strains and in most of the cases (76%), the percentage of red colonies suggested that both p53 alleles were inactivated. Sequencing analysis allowed the identification of a p53 mutation in each positive sample, and the spectrum of mutations was in agreement with the etiological role of tobacco and alcohol. These results confirm the high frequency of biallelic p53 mutations in esophageal carcinoma and strongly suggest that their biological consequence is the complete alteration of the transactivation of genes involved in the cell cycle and apoptosis, which indicates that p53 alteration is a key event in esophagus carcinogenesis.