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Wild type N-ras as a tumor suppressor in human sporadic medullary thyroid cardnoma

野生型 N-ras 作为人类散发性甲状腺髓样癌的肿瘤抑制因子

基本信息

批准号：
18390101
负责人：
TAKAHASHI Chiaki
金额：
$ 10.45万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Aberration of the retinoblastoma (Rb) pathway critically pertains to human carcinogenesis. However, the genetic evidence of Rb inactivation is found in an unexpectedly limited variety of malignant tumors, implicating a requirement of additional changes for robust clonal expansion by Rb-deficient cells. Rb-heterozygous mice produce C-cell adenoma in thyroid as a consequence of biallelic loss of Rb. We previously reported that additional deletion of N-ras in Rb-heterozygous mice resulted in malignant conversion in C-cell adenoma. To clarify the mechanism underlying the tumor suppressor function of wild type N-ras, we intensively characterized primary tumors from our genetically modified mice and also from human medullary thyroid carcinoma patients. As the results of our study, we propose here the mechanism by which at least murine C-cells and fibroblasts are protected from Rb-loss-induced carcinogenesis by the presence of N-ras loci. In the absence of Rb, N-Ras activity is increased in E2F-dependent manner, inducing DNA damage response and cellular senescence yet in a manner clearly distinct from its constitutively activated form. These findings assign a critical role for wild type N-ras in controlling malignant conversion of tumors upon pRb inactivation. In human sporadic medullary thyroid carcinomas in which ret oncogene mutation is less frequent than in familial cases, we previously detected 10 cases with Rb-N-ras double LOH out of 18 cases by using micro satellite markers flanking each gene. In this study, we obtained more number of samples (18 adenocarcinomas and 2 adenomas) from Tokyo Women's Medical College in an aim to perform more detailed immunohistochemical and genetic analyses. This line of investigation addresses whether N-ras acts as tumor suppressor in human cancers. Currently, we are acutely accumulating considerable amount of information from newly obtained clinical samples.

视网膜母细胞瘤（Rb）通路的畸变与人类致癌作用密切相关。然而，Rb失活的遗传证据被发现在一个意想不到的有限的各种恶性肿瘤，暗示了一个强大的克隆扩增Rb缺陷细胞的额外的变化的要求。Rb-杂合子小鼠产生甲状腺C-细胞腺瘤作为Rb双等位基因丢失的结果。我们以前曾报道，Rb杂合子小鼠中N-ras的额外缺失导致C细胞腺瘤的恶性转化。为了阐明野生型N-ras的肿瘤抑制功能的机制，我们深入研究了转基因小鼠和人甲状腺髓样癌患者的原发性肿瘤。作为我们的研究结果，我们在这里提出的机制，其中至少鼠C-细胞和成纤维细胞的保护Rb损失诱导的致癌作用的存在下的N-ras基因座。在不存在Rb的情况下，N-Ras活性以E2 F依赖的方式增加，诱导DNA损伤反应和细胞衰老，但其方式明显不同于其组成性激活形式。这些研究结果分配一个关键的作用，野生型N-ras在控制肿瘤的恶性转化后，pRb失活。在散发性甲状腺髓样癌中，ret癌基因突变频率低于家族性病例，我们以前用每个基因侧翼的微卫星标记检测了18例中的10例Rb-N-ras双洛缺失。在这项研究中，我们从东京女子医科大学获得了更多的样本（18个腺癌和2个腺瘤），目的是进行更详细的免疫组化和遗传分析。这条线的调查地址是否N-ras作为肿瘤抑制剂在人类癌症。目前，我们正在从新获得的临床样本中积累大量信息。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

RECK modulates the Notch signal during cortical neurogenesis

RECK 在皮质神经发生过程中调节 Notch 信号

DOI：
发表时间：
2007
期刊：
Nature Neuroscience 10 :
影响因子：
0
作者：
T.;Muraguchi;Y.;Takegami;E. P. S.;Chandana;S.;Kitajima;A.;Omura;T.;Mild;R.;Takahashi;N.;Matsumoto;A.;Ludwig;M.;Noda,C.;Takahashi
通讯作者：
Takahashi

ADAM10阻害因子RECK によるNotchシグナル伝達系制御

ADAM10 抑制剂 RECK 对 Notch 信号系统的调节