THE ROLE OF THE SIGNAL TRANSDUCERS IN TUMORIGENESIS

信号传感器在肿瘤发生中的作用

• 批准号: 6260264
• 负责人: CORINNE M SILVA
• 金额: $ 15.7万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6260264
• 关键词: JAK kinase; biological signal transduction; breast neoplasms; carcinogenesis; clinical research; enzyme activity; epidermal growth factor; female; fibroblasts; gene targeting; genetically modified animals; growth factor receptors; human subject; laboratory mouse; neoplasm /cancer genetics; phosphoproteins; protein tyrosine kinase; transcription factor; women's health

DESCRIPTION: (Adapted from the investigator's abstract) Tumorigenesis is a multi-step process the results in uncontrolled proliferation, invasion, and ultimately metastasis of tumor cells. This process frequently involves overexpression of signaling molecules otherwise involved in normal cellular proliferation and differentiation. Overexpression of the human epidermal growth factor receptor family (HER1/EGFR, HER2/neu, HER3, HER4) occurs in approximately 67 percent of human breast cancers. Overexpression of the non-receptor tyrosine kinase, c-Src, is found in close to 100 percent of breast tumors, and thus frequently accompanies EGFR overexpression. Since c-Src has been shown to potentiate EGF dependent DNA-synthesis in normal cells, co-overexpression of c-Src and EGFR in breast tumors suggests that c-Src may potentiate the role of HER family members in tumorigenesis. Human breast tumor cell lines which overexpress the EGFR and c-Src are characteristic of later stage tumors and poor prognosis. Identification of the downstream signaling molecules that are activated by overexpression of these two tyrosine kinases would provide targets for therapeutic intervention. The signal transducers and activators of transcription (STATs) are proteins that transmit a signal from a cytokine or growth factor receptor at the membrane of the cell to the nucleus where gene transcription is regulated. STATs are normally involved in the cellular process of proliferation, differentiation and apoptosis. Our preliminary evidence demonstrates that STAT proteins are activated in cells which overexpress the EGFR and c-Src in a manner dependent on EGFR kinase activity and c-Src mediated phosphorylation of the EGFR. Our hypothesis is that STAT proteins are one means by which a synergistic signal activated by EGFR and c-Src overexpression is transmitted to increase cell proliferation, transformation, and tumorigenesis. The following Specific Aims address this hypothesis: 1) Investigate the molecular mechanism of STAT5 activation in two tumorigenesis model systems; 2) Determine the role of STAT5 in transmitting the signal which leads to tumor function. The ultimate goal is that these studies will lead to the identification of novel therapeutic methods and/or reagents for treating breast cancer.

描述：（改编自研究者的摘要）肿瘤发生是一个 多步骤过程导致不受控制的增殖、入侵和 最终导致肿瘤细胞转移。这个过程经常涉及到 信号分子过度表达，否则参与正常细胞 增殖和分化。人类表皮生长的过度表达 因子受体家族（HER1/EGFR、HER2/neu、HER3、HER4）发生于 大约 67% 的人类乳腺癌。过度表达 非受体酪氨酸激酶 c-Src 存在于接近 100% 的乳房中 肿瘤，因此经常伴随 EGFR 过度表达。由于 c-Src 有 已被证明可以增强正常细胞中 EGF 依赖性 DNA 合成， c-Src 和 EGFR 在乳腺肿瘤中的共过表达表明 c-Src 可能 增强 HER 家族成员在肿瘤发生中的作用。人类乳腺肿瘤 过度表达 EGFR 和 c-Src 的细胞系是后来的特征 肿瘤分期，预后不良。下游信令识别 通过这两种酪氨酸激酶的过度表达而激活的分子 将为治疗干预提供目标。信号转换器和 转录激活剂 (STAT) 是从转录因子传递信号的蛋白质 细胞膜至细胞核的细胞因子或生长因子受体 基因转录受到调节的地方。 STAT 通常涉及 细胞的增殖、分化和凋亡过程。我们的 初步证据表明 STAT 蛋白在细胞中被激活 以依赖于 EGFR 激酶的方式过度表达 EGFR 和 c-Src EGFR 的活性和 c-Src 介导的磷酸化。我们的假设是 STAT 蛋白是 EGFR 和 EGFR 激活协同信号的一种手段。 c-Src 过度表达被传递以增加细胞增殖， 转化和肿瘤发生。以下具体目标解决了这个问题 假设：1）研究两种情况下STAT5激活的分子机制 肿瘤发生模型系统； 2) 确定STAT5在传输中的作用 导致肿瘤功能的信号。这些研究的最终目标是 将导致新的治疗方法和/或试剂的鉴定 用于治疗乳腺癌。