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

研究项目2：CK2和Wnt信号通路在进展中的作用

• 批准号: 7522917
• 负责人: DAVID C SELDIN
• 金额: $ 28.61万
• 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: 2008-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7522917
• 关键词: Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Biological Models; Carcinogens; Cell Adhesion Molecules; Cell Line; Cells; Chemosensitization; Collaborations; Colon Carcinoma; Data; Development; Disseminated Malignant Neoplasm; Dominant-Negative Mutation; Embryo; Environmental Carcinogens; Epithelial; Event; Exposure to; FVB Mouse; Funding; Genes; Genetic; Genetic Determinism; Grant; Heat-Shock Response; Human; In Vitro; Invasive; Kinetics; Laboratories; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Modeling; Morphology; Mus; Mutation; Neoplasm Metastasis; Oncogenic; Pathway interactions; Phenotype; Phosphotransferases; Play; Process; Protein Overexpression; Protein-Serine-Threonine Kinases; Proteins; Published Comment; RNA; RNA Splicing; Reagent; Regulation; Reporter; Reporting; Research Project Grants; Role; Signal Pathway; Signal Transduction; Staging; System; Techniques; Testing; Therapeutic Intervention; Transformed Cell Line; Transgenic Mice; Transgenic Organisms; Tumor Cell Invasion; Tumor Cell Line; Up-Regulation; Xenopus laevis; carcinogenesis; casein kinase II; dimethylbenzanthracene; epithelial to mesenchymal transition; in vivo; inhibitor/antagonist; interest; malignant breast neoplasm; neoplastic cell; prevent; promoter; research study; response; snail protein; tumor; tumor progression; tumorigenesis

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.

项目2关注蛋白激酶CK 2（酪蛋白激酶II）和Wnt信号通路的相互作用 在乳腺肿瘤发生过程中与致癌物的接触。在上一个授予期间，我们证明了 丝氨酸-苏氨酸激酶CK 2和GSK 3 β对Wnt信号传导具有相反的作用， 和激酶失活（K1）形式的GSK 3 β可促进体内乳腺肿瘤发生， 激活Wnt信号。与我们的P01合作者，我们建立了一个致癌物诱导的模型， FVB小鼠的乳腺肿瘤发生，并发现Wnt信号，CK 2，芳香烃 受体和肿瘤中的NF-κ B。因此，CK 2的激活和GSK 33的抑制被证明是 具有促进乳腺肿瘤发生和调节多种信号传导的潜力 途径。这种更新的中心假设是CK 2和Wnt信号是组成性激活的。 乳腺癌中的遗传和表观遗传事件，是上皮细胞向间质细胞转化的调节因子 （EMT）。导致肿瘤侵袭和转移。这一假设将通过三个具体的测试 目标：目标1。我们将研究一种典型的多环芳烃DMBA与CK 2的相互作用 和体内Wnt信号转导，使用MMTV-CK 2a转基因小鼠和LEF-EGFP Wnt报告基因转基因小鼠。 目标2.肿瘤进展的特征之一是正常上皮形态的丧失和上皮细胞的改变。 细胞粘附分子，通过EMT的过程。为此，我们将探讨 CK 2和NF-κ B协同促进EMT表型，并确定拮抗CK 2是否能 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 暴露于致癌物后CK 2上调的机制。动力学、调节水平和 将评估CK 2上调过程中AhR、NF-κ B和Wnt信号传导的需要。 意义：识别肿瘤进展为EMT样表型过程中的协同事件 对于预防或治疗侵袭性和/或转移性癌症具有巨大的转化潜力。如果激酶 是模型系统中的重要贡献者，有证据表明这也可能是人类乳房的情况 癌症，它提供了一个潜在的治疗干预的目标。