Identification of cooperating genes in tumorigenesis

肿瘤发生中协同基因的鉴定

• 批准号: 6719076
• 负责人: Helena Elizabeth Richardson
• 金额: $ 10万
• 依托单位: PETER MACCALLUM CANCER CENTRE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6719076
• 关键词: Drosophilidae; biological signal transduction; carcinogenesis; cell proliferation; eye neoplasms; gene expression; genetic screening; guanine nucleotide binding protein; neoplasm /cancer genetics; neoplastic process; oncogenes; phenotype; terminal nick end labeling; tumor suppressor genes

DESCRIPTION (provided by applicant) Cancer is a multigenic disease affecting 1/3 people at some point in their lifetime. Cancer is a multi-step process that relies on the successive mutations of key signaling, cell cycle or cell adhesion pathways to generate metastatic tumors. Since cancer arises from mostly normal cells and develops surrounded by normal cells, which are known to be involved in tumorigenic process, it is highly important to study the process of tumorigenesis in vivo. We propose here, to examine the process of tumorigenesis by using an unbiased approach in a whole non-mammalian animal model system, that of the vinegar fly, Drosophila. Due to the evolutionary conservation of signaling, cell cycle and cell adhesion pathways, studies carried out in Drosophila are highly relevant to mammals. We will examine 2 tumor suppressor genes, scribble and D-cbl and the oncogene, activated ras (ras-ACT), in the process of tumorigenesis. These genes function via different pathways in cellular regulation. Scribble is a scaffolding protein involved in apical-basal polarity, but may also have a role in modulating intracellular signaling. Cbl is an E3 ubiquitin ligase involved in down-regulation of transmembrane receptor signaling. ras is a signaling GTPase that acts downstream of growth factor receptors. We have shown that ras-ACT cooperates with scribble and D-cbl mutants to enhance their tumorigenic phenotypes. The overall aim of this proposal is to use the semi-neoplastic phenotypes generated by clones of scribble, D-cbl or ras-ACT mutants within a wild-type background to investigate the process of tumorigenesis in vivo. Specifically, the aims of this project are to: (1) Identify genes that when over-expressed cooperate with the scribble, D-cbl or ras-ACT mutants in inducing neoplasia, by using phenotypes generated by clones of these mutants in the Drosophila eye. These screens will allow us to systematically identify novel cooperating oncogenes in a whole animal system. (2) Identify genes when over-expressed specifically in wild-type tissue (but not in the scribble mutant tissue) rescue or enhance the phenotype caused by scribble-induced neoplasia in the eye. This screen will allow us to systematically identify genes that are expressed in wild-type cells that can act as tumor-promoting or anti-tumor genes. These screens will enable us to identify novel cooperating cancer-causing genes and anti-tumor genes within a whole animal system. The ultimate goal is to use this knowledge as a means to develop new targets for anti-cancer therapy.

描述（由申请人提供）癌症是一种多基因疾病，一生中某个时候影响1/3人。癌症是一个多步过程，依靠关键信号，细胞周期或细胞粘附途径的连续突变来产生转移性肿瘤。由于癌症主要是由正常细胞引起的，并被正常细胞所包围（已知与肿瘤过程有关），因此研究体内肿瘤发生过程非常重要。我们在这里建议通过在整个非哺乳动物动物模型系统（醋果蝇）中使用无偏的方法来检查肿瘤发生的过程。由于信号传导，细胞周期和细胞粘附途径的进化保护，在果蝇中进行的研究与哺乳动物高度相关。在肿瘤发生过程中，我们将检查2个肿瘤抑制基因，即涂鸦和D-CBL以及癌基因活化的Ras（Ras-ACT）。这些基因通过细胞调节中的不同途径发挥作用。涂鸦是参与顶端极性的脚手架蛋白，但也可能在调节细胞内信号传导中起作用。 CBL是参与跨膜受体信号下调的E3泛素连接酶。 RAS是一种信号GTPase，其作用于生长因子受体的下游。我们已经表明，RAS-ACT与涂鸦和D-CBL突变体合作，以增强其肿瘤性表型。该提案的总体目的是使用在野生型背景下由涂鸦，D-CBL或RAS-ECT突变体产生的半神经表型来研究体内肿瘤发生的过程。具体而言，该项目的目的是： （1）确定当过表达过表达时，通过使用果蝇眼中这些突变体的克隆产生的表型与诱导肿瘤中的涂鸦，D-CBL或Ras-act突变体合作。这些屏幕将使我们能够系统地识别整个动物系统中的新型肿瘤基因。 （2）当在野生型组织（但不能在涂鸦突变组织中）特别表达过表达时，鉴定基因营救或增强由涂鸦引起的眼睛中的肿瘤引起的表型。该屏幕将使我们能够系统地鉴定在野生型细胞中表达的基因，这些基因可以充当肿瘤或抗肿瘤基因。 这些筛选将使我们能够在整个动物系统中鉴定出新的致癌基因和抗肿瘤基因的合作。最终目标是利用这些知识作为开发抗癌治疗目标的一种手段。

项目成果

The BTB-zinc finger transcription factor abrupt acts as an epithelial oncogene in Drosophila melanogaster through maintaining a progenitor-like cell state.

• DOI: 10.1371/journal.pgen.1003627
• 发表时间: 2013
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Turkel N;Sahota VK;Bolden JE;Goulding KR;Doggett K;Willoughby LF;Blanco E;Martin-Blanco E;Corominas M;Ellul J;Aigaki T;Richardson HE;Brumby AM
• 通讯作者: Brumby AM

New tricks for old dogs: unexpected roles for cell cycle regulators revealed using animal models.

老狗的新技巧：使用动物模型揭示细胞周期调节剂的意想不到的作用。

• DOI: 10.1016/j.ceb.2004.09.001
• 发表时间: 2004
• 期刊: Current opinion in cell biology.
• 作者: Humbert,PatrickO;Brumby,AnthonyM;Quinn,LeonieM;Richardson,HelenaE
• 通讯作者: Richardson,HelenaE