PHOSPHORYLATION OF BETA-CATENIN

β-连环蛋白的磷酸化

• 批准号: 7723059
• 负责人: DAVID C SELDIN
• 金额: $ 0.32万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7723059
• 关键词: Biology; Breeding; Carcinogens; Catalytic Domain; Cells; Chronic Myeloid Leukemia; Computer Retrieval of Information on Scientific Projects Database; Defect; Development; Embryo; Engineering; Enzymes; Exhibits; Funding; Gleevec; Grant; Human; Imatinib; In Vitro; Institution; Knock-out; Lymphoid Cell; Lymphoma; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Modeling; Mus; Oncogene Proteins; Oncogenes; Oncogenic; Pathway interactions; Pattern; Phase; Phosphorylation; Phosphotransferases; Pregnancy; Protein Overexpression; Protein-Serine-Threonine Kinases; Research; Research Personnel; Resources; Role; Signal Pathway; Signal Transduction; Source; Techniques; Therapeutic; Transgenic Model; Transgenic Organisms; United States National Institutes of Health; beta catenin; cancer therapy; homologous recombination; in vitro Model; in vivo; novel; novel therapeutics; research study; tandem mass spectrometry; tool; tumor; tumorigenesis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have been studying the oncogenic potential of the regulatory serine-threonine kinase CK2, a tetrameric enzyme that is highly evolutionary conserved and overexpressed in many human cancers. In transgenic models, we have shown that CK2 produces lymphomas when overexpression is directed to lymphoid cells, and mammary tumors when directed to the mammary gland. CK2-induced tumors exhibit activation of signaling pathways including the Wnt and NF-KB pathways, and we have shown that CK2 is an activator of those and other pro-oncogenic pathways. We are using homologous recombination and other techniques to elucidate the role of CK2 in Wnt signaling during development and tumorigenesis. We have developed "knockouts" for the two catalytic subunits of CK2. Recently, we have shown that CK2a-/- embryos die in mid-gestation. We are now focusing upon characterizing the defects in the CK2 -/- embryos and using them and other tools to elucidate the essential functions of CK2. We are determining the developmental role of CK2 and examining the status of targets of CK2 in the knockout embryos and in MEFs derived from them. We are determining the role of CK2 in Wnt signaling in cells. We are crossing creating CK2 compound knockouts with graded levels of catalytic CK2 expression, and we arel engineering mice with a conditional CK2 knockout in the mammary gland. These mice are being bred with Wnt pathway oncogene transgenics and treated with carcinogens to determine whether CK2 expression is required for in vivo tumorigenesis; the role of CK2 in in vitro tumorigenesis models is also being assessed. These experiments shouldl allow us to fully explore the function of CK2 as a regulator of tumorigenesis and development, in in vivo and in vitro models. Kinases have proven to be suitable targets for novel cancer therapeutics. For example, the bcr-abl oncoprotein of chronic myelogenous leukemia is effectively inhibited by Imatinib (Gleevec). Since CK2 is upregulated in all human tumors that have been studied, CK2 may be a suitable target for cancer treatment. Understanding basic CK2 biology and signaling is a necessary prelude to developing novel therapeutics against it. In one phase of these explorations, tandem mass spectrometry is being used to assess the phosphorylation pattern of beta-catenin.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们一直在研究调节丝氨酸-苏氨酸激酶CK2的致癌潜力，这是一种四聚体酶，在许多人类癌症中高度进化保守和过度表达。在转基因模型中，我们已经证明，当CK2过表达指向淋巴样细胞时会产生淋巴瘤，当过度表达指向乳腺时会产生乳腺肿瘤。CK2诱导的肿瘤表现出信号通路的激活，包括Wnt和NF-KB通路，我们已经证明CK2是这些和其他促肿瘤通路的激活剂。我们正在使用同源重组和其他技术来阐明CK2在Wnt信号通路中在发育和肿瘤发生中的作用。我们已经为CK2的两个催化亚基开发了“敲除”。最近，我们发现CK2a-/-胚胎在妊娠中期死亡。我们现在正专注于鉴定CK2-/-胚胎中的缺陷，并使用它们和其他工具来阐明CK2的基本功能。我们正在确定CK2的发育作用，并检测CK2靶标在基因敲除胚胎及其衍生的MEF中的地位。我们正在确定CK2在细胞中Wnt信号转导中的作用。我们正在交叉创建CK2复合基因敲除和分级水平的催化CK2表达，我们正在利用乳腺中有条件的CK2基因敲除小鼠。这些小鼠是用Wnt途径的癌基因转基因培育的，并用致癌物治疗，以确定CK2的表达是否是体内肿瘤发生所必需的；也正在评估CK2在体外肿瘤发生模型中的作用。这些实验应该允许我们在体内和体外模型中充分探索CK2作为肿瘤发生和发展的调节因子的功能。激酶已被证明是新的癌症治疗方法的合适靶点。例如，慢性粒细胞白血病的bcr-abl癌蛋白可被伊马替尼(格列卫)有效抑制。由于CK2在所有已研究的人类肿瘤中表达上调，CK2可能是癌症治疗的合适靶点。了解CK2的基本生物学和信号转导是开发新的治疗方法的必要前奏。在这些探索的一个阶段，串联质谱仪被用来评估β-连环蛋白的磷酸化模式。