Research Project 2: Role of CK2 and the Wnt Signaling Pathway in the Progression

项目2重点研究蛋白激酶CK2(酪蛋白激酶II)与Wnt信号通路的相互作用 与致癌物一起参与了乳腺肿瘤的发生过程。在之前的授权期内，我们展示了 丝氨酸苏氨酸激酶CK2和GSK3(3)对Wnt信号有相反的作用，而CK2 和一种Kl形式的GSK3(3可以促进体内乳腺肿瘤的形成)，这与 带有激活的WNT信号。与我们的P01合作者一起，我们建立了致癌物诱导的模型 FVB小鼠乳腺肿瘤发生及Wnt信号、芳香烃CK2的上调 受体和核因子-kB在肿瘤中的表达。因此，CK2的激活和GSK33的抑制被证明是 有可能参与乳腺肿瘤的发生和多种信号的调节 小路。这种更新的中心假设是CK2和Wnt信号是结构性激活的 通过乳腺癌中的遗传和表观遗传事件，是上皮向间充质转化的调节因素 (EMT)。导致肿瘤侵袭和转移。这一假设将通过三个具体的 目的：目的1.研究一种典型的多环芳烃DMBA与CK2的相互作用 体内Wnt信号转导，使用MMTV-CK2a转基因小鼠和Lef-EGFP Wnt报告基因小鼠。 目的2.肿瘤进展的特征之一是失去正常的上皮形态和改变 细胞黏附分子，通过EMT过程。在这个目标中，我们将探索通过以下机制 CK2和NF-KB协同促进EMT表型，并确定拮抗CK2是否可以 逆转肿瘤细胞的侵袭和/或转移表型。目标3。在这里我们将调查 致癌物暴露后CK2上调的机制。动力学、调控水平和 将评估在CK2上调过程中对AhR、NF-KB和Wnt信号的需求。 意义：确定肿瘤进展为EMT样表型过程中的协同事件 在预防或治疗浸润性和/或转移性癌症方面具有巨大的转化潜力。如果一种激活剂 是模型系统的重要贡献者，有证据表明这可能也是人类乳房的情况 癌症，它为治疗干预提供了一个潜在的靶点。

Project 2 focuses on the interaction of protein kinase CK2 (casein kinase II) and the Wnt signaling pathway with carcinogens in the process of mammary tumorigenesis. In the prior granting period, we demonstrated that the serine-threonine kinases CK2 and GSK3(3 have opposing effects on Wnt signaling, and that CK2 and a kinase inactive (Kl) form of GSK3(3 can promote mammary tumorigenesis in vivo that is associated with activated Wnt signaling. With our P01 collaborators, we established a model of carcinogen-induced mammary tumorigenesis in FVB mice, and found upregulation of Wnt signaling, CK2, the aryl hydrocarbon receptor, and NF-KB in the tumors. Thus, activation of CK2 and inhibition of GSK33 are demonstrated to have the potential to contribute to mammary tumorigenesis and to the regulation of multiple signaling pathways. The central hypothesis of this renewal is that CK2 and Wnt signaling are constitutivelv activated by genetic and epiqenetic events in breast cancer and are regulators of epithelial to mesenchymal transition (EMT). leading to tumor invasion and to metastasis. This hypothesis will be tested through three specific aims: Aim 1. We will study the interaction of a prototypical polycyclic aromatic hydrocarbon, DMBA with CK2 and Wnt signaling in vivo, using MMTV-CK2a transgenic mice and LEF-EGFP Wnt reporter transgenic mice. Aim 2. One of the features of tumor progression is the loss of normal epithelial morphology and alteration in cell adhesion molecules, through the process of EMT. In this aim we will explore the mechanism by which CK2 and NF-KB collaborate to promote the EMT phenotype, and determine whether antagonizing CK2 can reverse the invasive and/or metastastatic phenotype of tumor cells. Aim 3. Here we will investigate the mechanism of upregulation of CK2 after exposure to carcinogens. The kinetics, level of regulation, and requirement for AhR, NF-KB, and Wnt signaling in the process of upregulation of CK2 will be assessed. Signficance: Identifying collaborating events in the process of tumor progression to the EMT-like phenotype is of tremendous translational potential for preventing or curing invasive and/or metastatic cancer. If a kinase is an important contributor in model systems, with evidence that this may also be the case in human breast cancer, it provides a potential target for therapeutic intervention.