A Drosophila Model for Src-Mediated Oncogenesis

Src 介导的肿瘤发生的果蝇模型

• 批准号: 6820768
• 负责人: Ross Leigh Cagan
• 金额: $ 24.85万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6820768
• 关键词: Drosophilidae; apoptosis; biological models; biological signal transduction; cell cycle; enzyme activity; genetic screening; model design /development; multiple endocrine neoplasia; neoplasm /cancer genetics; neoplastic process; polymerase chain reaction; protooncogene; terminal nick end labeling

DESCRIPTION (provided by applicant): During epithelial maturation, a large number of signal transduction molecules are utilized to regulate cell cycle and cell death. When activated by mutation these same factors can provoke uncontrolled growth, a common step in the development of cancer. For example, activating mutations in the Ret receptor tyrosine kinase can provoke oncogenic diseases such as Multiple Endocrine Neoplasia Type 2 (MEN2). By targeting analogous forms of activated Ret to the developing Drosophila retina, an in vivo model was developed to explore the downstream signaling components that are responsible for aspects of the MEN2 disease. This approach identified several pathways that, when mutated, alter the outcome of Ret activation. The importance of these pathways in human tumor tissue is currently being explored. One downstream pathway that modified the Ret (MEN2) phenotype was the Src signaling pathway. Src is a cytoplasmic kinase that has been linked to dozens of cancer types including those of the colon and breast, as well as blood-based cancers. C-terminal Src kinase (Csk) is the major inhibitor of Src signaling. Reducing Drosophila Csk activity led to activation of Src and a concomitant cell-autonomous activation of the cell cycle, which in turn led to uncontrolled growth. The result was an enlarged, abnormally patterned eye. Importantly, reducing activity of the STAT signaling pathway prevented this oncogenic growth: mutations in Drosophila STAT led to death of otherwise proliferative Csk tissue. This suggests a strategy for therapeutic intervention of tumors that contain an activated Src pathway. This Proposal seeks to better understand the nature of STAT's ability to kill Csk-deficient cells by using genetic screens to identify 'killing' pathways. In addition, the role of Src signaling downstream of a number of receptors will be further explored. Finally, the advantages of the Drosophila retina as a sensitive assay of signaling, overgrowth, and cell death will be exploited as an in vivo screen for drugs that can also ameliorate Csk/Src-mediated overgrowth.

描述（由申请人提供）：在上皮成熟期间，大量信号转导分子用于调节细胞周期和细胞死亡。当突变激活时，这些相同的因素会引起不受控制的生长，这是癌症发展的常见步骤。例如，在RET受体酪氨酸激酶中激活突变会引起致癌性疾病，例如多种内分泌肿瘤2型（MEN2）。通过将类似形式的激活RET靶向发展到发展中的果蝇视网膜，开发了一个体内模型，以探索负责MEN2疾病方面的下游信号传导成分。该方法确定了几种途径，当突变时会改变RET激活的结果。目前正在探索这些途径在人类肿瘤组织中的重要性。 修改RET（MEN2）表型的下游途径是SRC信号通路。 SRC是一种细胞质激酶，与数十种癌症类型有关，包括结肠和乳腺癌以及血液基癌。 C末端SRC激酶（CSK）是SRC信号传导的主要抑制剂。降低果蝇CSK活性导致SRC的激活和伴随的细胞自主激活，从而导致不受控制的生长。结果是肿大，异常的眼睛。重要的是，降低统计信号通路的活性阻止了这种致癌生长：果蝇的突变导致原本增殖的CSK组织死亡。这表明了包含活化SRC途径的肿瘤治疗干预的策略。 该提案旨在通过使用遗传筛选来识别“杀死”途径来更好地理解Stat杀死CSK缺陷细胞的能力的性质。另外，将进一步探讨许多受体下游的SRC信号传导的作用。最后，果蝇视网膜作为信号，过度生长和细胞死亡的敏感测定法的优势将被用作药物的体内筛查，也可以改善CSK/SRC介导的过度生长。