Clinical significance of oncogenic mutations of p53 gene in oral cancen : Relationship of the mutations with radiation- and chemo-sensitivity

口腔癌中p53基因致癌突变的临床意义：突变与放射和化疗敏感性的关系

• 批准号: 15592131
• 负责人: KAWAMATA Hitoshi
• 金额: $ 2.24万
• 依托单位: Dokkyo University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15592131/
• 关键词: oral cancer; p53; oncogenic mutation; chemosensitivity; radiation sensitivity; p73; 抗癌感受性

We examined the functional diversity of several mutant-p53 derived from human head and neck cancer cell lines. Entire open reading frame of p53 cDNA was subcloned into a mammalian expression vector, and genetic mutations were determined. Then, their intracellular localization, transcriptional activity, and oncogenic function were examined in a human osteosarcoma cell line lacking p53 gene, Saos-2 cells. A mutant-p53 (Glu17Lys,His193Leu) or a truncated-p53 (delta 121) did not activate the reporters containing p53 responsive elements from p21waf1,BAX,MDM2,p53AIP, and PUMA genes. However, a mutant-p53 (Asn30Ser) showed the transcriptional activity on all of the reporters. On the other hand, a mutant-p53 (Asp28lHis) activated the p21waf1 promoter strongly and the MDM2 promoter faintly, but did not activate the BAX promoter. Interestingly, this mutant-p53 prevented Saos-2 cells from undergoing apoptosis after treatment with a DNA damaging agent, adriamycin. This mutant-p53 strongly induced cell cycle arrest but marginally induced apoptosis. Another mutant-p53 (Glu17Lys,His193Leu) also prevented the cells from undergoing apoptosis after DNA damage probably in a transcription-independent manner. These results suggest that some head and neck cancer cell lines contain the oncogenic mutation of p53 gene, and the oncogenic p53 protein prevents cancer cells from undergoing apoptosis after DNA damage.

我们研究了几种来源于人头颈癌细胞系的突变型p53的功能多样性。将p53 cDNA的完整开放阅读框架亚克隆到哺乳动物表达载体中，并确定基因突变。然后，他们的细胞内定位，转录活性，并在人骨肉瘤细胞系缺乏p53基因，Saos-2细胞的致癌功能进行了检查。突变型p53（Glu 17 Lys，His 193 Leu）或截短型p53（delta 121）不能激活含有p53应答元件的报告基因，这些元件来自p21 waf 1、BAX、MDM 2、p53 AIP和p53 A基因。然而，突变体p53（Asn 30 Ser）显示对所有报告基因的转录活性。另一方面，突变型p53（Asp 28 lHis）强烈激活p21 waf 1启动子，微弱激活MDM 2启动子，但不激活BAX启动子。有趣的是，这种突变p53阻止Saos-2细胞在用DNA损伤剂阿霉素处理后发生凋亡。这种突变体p53强烈诱导细胞周期停滞，但轻微诱导细胞凋亡。另一种突变体p53（Glu 17 Lys，His 193 Leu）也可能以非转录依赖的方式阻止DNA损伤后的细胞凋亡。这些结果表明，某些头颈癌细胞系中存在p53基因的致癌突变，致癌p53蛋白阻止了DNA损伤后的癌细胞凋亡。

项目成果

Frequent Down-regulation of 14-3-3 σ protein and Hypermethylation of 14-3-3 σ gene in Salivary Gland Adenoid Cystic Carcinoma.

唾液腺腺样囊性癌中 14-3-3 σ 蛋白频繁下调和 14-3-3 σ 基因高甲基化。

• 发表时间: 2004
• 期刊: British Journal of Cancer. 91(6)
• 作者: Uchida D;Begum N-M;Almofti A;Yoshida H;Sato M.
• 通讯作者: Sato M.

Kawamata H., Furihata T., Omotehara F., et al.: "Identification of genes differentially expressed in a newly isolated human metastasizing esophageal cancer cell line, T.Tn-AT1,by CDNA microarray."Cancer Sci.. 94・8. 699-706 (2003)

Kawamata H.、Furihata T.、Omotehara F. 等人：“通过 CDNA 微阵列鉴定新分离的人类转移性食管癌细胞系 T.Tn-AT1 中差异表达的基因。”Cancer Sci.. 94。 8. 699-706 (2003)

Oncogenic mutation of p53 gene derived from head and neck cancer cell lines prevents cells from undergoing apoptosis after DNA damage

来自头颈癌细胞系的 p53 基因的致癌突变可防止细胞在 DNA 损伤后发生凋亡

• 发表时间: 2004
• 期刊: Br J Cancer (in press)
• 作者: Kawamata H;Omotehara F;Nakashiro K;Uchida D;Shinagawa Y;Tachibana M;Imai Y;Fujimori T.
• 通讯作者: Fujimori T.

Development of colonic neoplasia in p53-deficient mice with Experiment colitis induced by dextran sulfate sodium

右旋糖酐硫酸钠诱导实验性结肠炎 p53 缺陷小鼠结肠肿瘤的发生

• 发表时间: 2004
• 期刊: Gut 53・5
• 作者: Fujii S;Kawamata H;et al.
• 通讯作者: et al.

Horiuchi H, Kawamata H, Omotehara F, et al.: "Negative Immunohistochemical staining of p53 protein does not always reflect wild type p53 gene in cancer cells."J Gastroenterol. 印刷中.

Horiuchi H、Kawamata H、Omotehara F 等人：“p53 蛋白的阴性免疫组织化学染色并不总是反映癌细胞中的野生型 p53 基因。”J Gastroenterol 出版。