Tau in cancer cells

癌细胞中的 Tau 蛋白

• 批准号: 7862457
• 负责人: Gloria Lee
• 金额: $ 15.38万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7862457
• 关键词: Accounting; Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antineoplastic Agents; Biological Models; Brain; Cancer Etiology; Cancer cell line; Cell Culture Techniques; Cell Cycle; Cell Cycle Regulation; Cell Death; Cell Nucleus; Cell Proliferation; Cell Survival; Cell division; Cells; Cessation of life; Cyclins; DNA biosynthesis; Data; Deposition; Disease; Drosophila genus; Drug resistance; Elements; Equilibrium; Estramustine; Genetic Transcription; Human; Laboratories; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of prostate; Mammalian Cell; Mediating; Mitosis; Mitotic; Modeling; Modification; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Oncogenes; Oncogenic; PC3 cell line; Paclitaxel; Pathology; Pharmaceutical Preparations; Phosphotransferases; Post-Translational Protein Processing; Process; Proteins; Regulation; Research; Resistance; Role; SV40 T Antigens; Senile Plaques; Signal Transduction; Signal Transduction Pathway; Site; Staging; Tauopathies; Testing; Transcription Factor AP-1; Transgenic Mice; Up-Regulation; Ursidae Family; age related; base; brain cell; brain tissue; cancer cell; cytotoxicity; fly; hyperphosphorylated tau; link protein; malignant breast neoplasm; mouse model; neuron loss; neuropathology; neurotoxicity; overexpression; public health relevance; receptor; response; src-Family Kinases; tau Proteins; tau expression; tau mutation; tau phosphorylation; tau-1; transcription factor

DESCRIPTION (provided by applicant): In many age-related neurodegenerative diseases, neuronal loss is correlated with the presence of hyperphosphorylated tau. In Alzheimer's disease, it has been hypothesized that neurons die because cell cycle mechanisms have been activated. In support of this hypothesis, the expression of oncogenes in neurons has caused cell death accompanied by DNA synthesis and the expression of cyclins. In addition, in a fly model for neurodegenerative disease, the death of neurons caused by the expression of hyperphosphorylated human tau could be modulated by cell cycle related proteins. Our laboratory has investigated an interaction between tau and Src family tyrosine kinases and has found that tau can activate these kinases, which are also oncogenes. This application is based on preliminary data showing that hyperphosphorylated tau is present in prostate cancer cells and that tau can potentiate the activation of AP-1, a transcription factor that functions in cell proliferation, survival, and transformation. We propose to use non-neuronal and neuronal cancer cells as model systems to investigate the function of hyperphosphorylated tau in signal transduction mechanisms that control the cell cycle. We will test the hypothesis that tau enhances the activation of AP-1 mediated transcription through its interaction with SFKs, which leads to increased cell proliferation. The specific aims are to (1) determine the role of tau in the regulation of AP-1 activity in cancer cells and (2) determine the effects of tau on cell viability in response to anti-cancer drugs. Resistance to anti-cancer drugs has been correlated with increased levels of tau in breast cancer and we hypothesize that in cancer cells, tau is affecting cell cycle mechanisms, antagonizing the mitotic block caused by the drugs, thereby resulting in drug resistance. In both aims, we will investigate the effects of tau depletion and tau overexpression. Because of the similarities between tau in Alzheimer's disease and tau in prostate cancer cells and the loss of cell cycle control in both age-related diseases, our ultimate aim is to determine if hyperphosphorylated tau is able to tip the balance in cell cycle control mechanisms towards cell division. In so doing, the results of this study will provide a new perspective towards the function of the pre-tangle hyperphosphorylated tau found at the early stages of neurodegenerative disease. PUBLIC HEALTH RELEVANCE: Alzheimer's disease and other age-related neurodegenerative diseases is characterized by the presence of brain lesions made of abnormal forms of tau protein. This application will investigate tau in cancer cell lines as we have discovered that this tau has similarities to the abnormal tau in Alzheimer's disease. Moreover, cancer cells have a loss of cell cycle control and a hypothesis in Alzheimer's disease research is that brain cells die because they have lost cell cycle control. The data from this application will further our understanding of how abnormal tau might lead to cell death.

描述（由申请人提供）：在许多年龄相关的神经退行性疾病中，神经元损失与过度磷酸化tau的存在相关。在阿尔茨海默病中，人们假设神经元死亡是因为细胞周期机制被激活。为了支持这一假说，神经元中癌基因的表达导致了伴随DNA合成和细胞周期蛋白表达的细胞死亡。此外，在神经退行性疾病的果蝇模型中，由过度磷酸化的人tau蛋白的表达引起的神经元死亡可以通过细胞周期相关蛋白来调节。我们的实验室研究了tau和Src家族酪氨酸激酶之间的相互作用，并发现tau可以激活这些激酶，这些激酶也是致癌基因。该申请基于初步数据，显示过度磷酸化的tau蛋白存在于前列腺癌细胞中，并且tau蛋白可以增强AP-1的激活，AP-1是一种在细胞增殖、存活和转化中起作用的转录因子。我们建议使用非神经元和神经元癌细胞作为模型系统，以研究过度磷酸化tau蛋白在控制细胞周期的信号转导机制中的功能。我们将检验tau通过与SFKs相互作用增强AP-1介导的转录激活的假设，这导致细胞增殖增加。具体目的是（1）确定tau在调节癌细胞中AP-1活性中的作用，以及（2）确定tau对抗癌药物应答的细胞活力的影响。对抗癌药物的耐药性与乳腺癌中tau水平的增加相关，我们假设在癌细胞中，tau影响细胞周期机制，拮抗药物引起的有丝分裂阻滞，从而导致耐药性。在这两个目标中，我们将研究tau耗竭和tau过表达的影响。由于阿尔茨海默病中的tau蛋白和前列腺癌细胞中的tau蛋白之间的相似性以及这两种年龄相关疾病中细胞周期控制的丧失，我们的最终目标是确定过度磷酸化的tau蛋白是否能够使细胞周期控制机制的平衡向细胞分裂倾斜。通过这样做，本研究的结果将为神经退行性疾病早期发现的缠结前过度磷酸化tau的功能提供新的视角。公共卫生相关性：阿尔茨海默病和其他与年龄相关的神经退行性疾病的特征在于存在由异常形式的tau蛋白构成的脑损伤。该应用将研究癌细胞系中的tau，因为我们已经发现这种tau与阿尔茨海默病中的异常tau具有相似性。此外，癌细胞失去了细胞周期控制，阿尔茨海默病研究中的一个假设是，脑细胞死亡是因为它们失去了细胞周期控制。这项应用的数据将进一步加深我们对异常tau蛋白如何导致细胞死亡的理解。