PHOSPHORYLATION OF BETA-CATENIN

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们一直在研究调节性丝氨酸-苏氨酸激酶CK 2的致癌潜力，CK 2是一种在许多人类癌症中高度进化保守和过表达的四聚体酶。在转基因模型中，我们已经表明，CK 2产生淋巴瘤时，过度表达是针对淋巴样细胞，乳腺肿瘤时，针对乳腺。CK 2诱导的肿瘤表现出包括Wnt和NF-κ B通路在内的信号通路的激活，我们已经证明CK 2是这些通路和其他促癌通路的激活剂。我们正在使用同源重组和其他技术来阐明CK 2在发育和肿瘤发生过程中Wnt信号传导中的作用。我们已经开发了CK 2的两个催化亚基的“敲除”。最近，我们已经表明，CK 2a-/-胚胎在妊娠中期死亡。我们现在专注于描述CK 2-/-胚胎中的缺陷，并使用它们和其他工具来阐明CK 2的基本功能。我们正在确定CK 2的发育作用，并检查CK 2在敲除胚胎和来自它们的MEFs中的靶点状态。我们正在确定CK 2在细胞中Wnt信号传导中的作用。我们正在交叉创建CK 2复合敲除与催化CK 2表达的分级水平，并且我们正在用乳腺中的条件性CK 2敲除来改造小鼠。这些小鼠与Wnt途径癌基因转基因小鼠一起饲养，并用致癌物处理，以确定体内肿瘤发生是否需要CK 2表达;还评估了CK 2在体外肿瘤发生模型中的作用。这些实验将使我们能够在体内和体外模型中充分探索CK 2作为肿瘤发生和发展的调节剂的功能。激酶已被证明是新型癌症治疗剂的合适靶标。例如，伊马替尼（格列卫）可有效抑制慢性粒细胞白血病的bcr-abl癌蛋白。由于CK 2在所有已研究的人类肿瘤中上调，因此CK 2可能是癌症治疗的合适靶点。了解CK 2的基本生物学和信号传导是开发新疗法的必要前提，在这些探索的一个阶段，串联质谱法被用来评估β-连环蛋白的磷酸化模式。

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.