Regulation of Tumor Cell Differentiation by Src Kinases

Src 激酶对肿瘤细胞分化的调节

• 批准号: 7254933
• 负责人: MALCOLM A MEYN
• 金额: $ 13.94万
• 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/7254933
• 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; Numbers; 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。由于分化通常与细胞周期的退出相协调，因此分化的丧失可能会导致表型的转变。启动分化途径并导致增殖能力丧失的癌症治疗为癌症控制提供了一种新方法。然而，许多癌症对分化疗法难以治疗或对当前使用的药物产生耐药性。对调节分化的信号通路以及分化和增殖之间存在的反向关系缺乏了解，阻碍了新型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，而小鼠胚胎干 (ES) 细胞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，我们将检验这样的假设：细胞 Src 激酶通常协调细胞周期的退出与鼠 ES 细胞的分化。其次，我们将检验这样的假设：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，如许多癌细胞中所见。第三，我们将检验以下假设：结肠癌细胞中常见的 Src 激酶活性升高有助于抑制分化，在某些情况下通过 Stat 依赖性机制。除了研究计划之外，还提出了发展申请人在人类癌症细胞信号传导领域的专业知识的提案。总之，完成这些目标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。 相关性：诱导细胞分化的药物已成功用于治疗有限数量的癌症。这里提出的工作旨在确定阻止癌细胞分化的生化途径。了解这些途径有助于设计新型治疗剂，有望将这种疗法扩展到新型癌症。