Regulation of Tumor Cell Differentiation by Src Kinases

Src 激酶对肿瘤细胞分化的调节

• 批准号: 7651291
• 负责人: MALCOLM A MEYN
• 金额: $ 16.1万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7651291
• 关键词: Address; Alleles; Basic Science; Biochemical Pathway; Cancer Control; Cell Cycle; Cell Cycle Progression; Cell Differentiation process; Cell Line; Cell Proliferation; Cells; Cellular biology; Chemicals; Colon Carcinoma; Data; Development; Differentiation Therapy; Differentiation and Growth; Family member; Future; Gene Targeting; Genes; Goals; Human; Individual; Knock-out; Lead; Malignant Neoplasms; Mus; Mutation; Normal Cell; Oncogenic; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Refractory; Regulation; Research; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Silent Mutation; System; Testing; Therapeutic Agents; Up-Regulation; Variant; Work; analog; anti-cancer therapeutic; base; cancer cell; cancer cell differentiation; cancer therapy; cancer type; career; cell transformation; design; embryonic stem cell; inhibitor/antagonist; kinase inhibitor; metaplastic cell transformation; neoplastic cell; novel; novel strategies; novel therapeutics; prevent; programs; research study; self-renewal; small molecule; src-Family Kinases; transcription factor; tumor

DESCRIPTION (provided by applicant): Lack of differentiation is a hallmark of many cancer cells. Because differentiation is often coordinated with exit from the cell cycle, loss of differentiation may contribute to the transformed phenotype. Cancer therapies that initiate differentiation pathways and result in a loss of proliferative capacity provide a novel approach to cancer control. Many cancers, however, are refractory to differentiation therapy or acquire resistance to currently utilized drugs. A lack of understanding about the signaling pathways that regulate differentiation and the inverse relationship that exists between differentiation and proliferation hinders the design of novel differentiation-inducing molecules. We propose to contribute to the understanding of these pathways by testing the hypothesis that oncogenic Src family kinases aberrantly activate signaling pathways that inhibit differentiation of pluripotent cells. Understanding differentiation and cell cycle exit in normal cells is vital for understanding the changes that occur in transformed cells and mouse embryonic stem (ES) cells provide an ideal system for studying these signaling pathways. Our work will involve three specific aims. First, we will test the hypothesis that cellular Src kinases normally coordinate exit from the cell cycle with differentiation in murine ES cells. Second, we will test the hypothesis that oncogenic Src kinases aberrantly activate Stat transcription factors and other pathways that suppress differentiation in ES cells as seen in many cancer cells. Third, we will test the hypothesis that elevated Src kinase activity commonly observed in colon cancer cells contributes to the inhibition of differentiation, in some cases through a Stat-dependent mechanism. In addition to the research plan, a proposal for the development of the Applicant's expertise in the field of cell signaling in human cancer is presented. Together, completion of these goals will serve to transition the Applicant to an independent career in the basic research of human cancer cell biology. Relevance: Drugs that induce cellular differentiation have been successfully used in the treatment of a limited number of cancers. The work proposed here seeks to identify biochemical pathways that prevent the differentiation of cancer cells. Understanding these pathways can aid in the design of novel therapeutic agents with the hope of expanding this type of therapy to new types of cancer.

描述（由申请人提供）：缺乏分化是许多癌细胞的标志。因为分化通常与退出细胞周期相协调，所以分化的丧失可能有助于转化的表型。启动分化途径并导致增殖能力丧失的癌症疗法为癌症控制提供了一种新方法。然而，许多癌症对分化疗法是难治的或对目前使用的药物获得抗性。缺乏对调节分化的信号通路以及分化和增殖之间存在的逆关系的理解阻碍了新的分化诱导分子的设计。我们建议通过测试致癌Src家族激酶异常激活抑制多能细胞分化的信号通路的假设来促进对这些通路的理解。了解正常细胞的分化和细胞周期退出对于了解转化细胞中发生的变化至关重要，小鼠胚胎干细胞（ES）为研究这些信号通路提供了理想的系统。我们的工作将涉及三个具体目标。首先，我们将测试的假设，细胞Src激酶通常协调退出细胞周期与小鼠ES细胞的分化。其次，我们将测试致癌Src激酶异常激活Stat转录因子和其他抑制ES细胞分化的途径的假设，如在许多癌细胞中所见。第三，我们将测试的假设，提高Src激酶活性通常在结肠癌细胞中观察到有助于抑制分化，在某些情况下，通过一个Stat-dependent机制。除了研究计划外，还提出了一项关于发展申请人在人类癌症细胞信号传导领域的专业知识的建议。总之，这些目标的完成将有助于申请人过渡到人类癌细胞生物学基础研究的独立职业生涯。 相关性：诱导细胞分化的药物已成功用于治疗数量有限的癌症。本文提出的工作旨在确定阻止癌细胞分化的生化途径。了解这些途径可以帮助设计新的治疗药物，希望将这种类型的治疗扩展到新类型的癌症。