Tau in cancer cells

描述（由申请人提供）：在许多与年龄相关的神经退行性疾病中，神经元丢失与过度磷酸化的tau蛋白的存在相关。在阿尔茨海默病中，假设神经元死亡是因为细胞周期机制被激活。为了支持这一假设，神经元中癌基因的表达导致细胞死亡，同时伴随着DNA合成和细胞周期蛋白的表达。此外，在神经退行性疾病的果蝇模型中，过度磷酸化的人tau表达引起的神经元死亡可以通过细胞周期相关蛋白调节。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，发现tau可以激活这些激酶，这些激酶也是致癌基因。这一应用是基于初步数据显示过度磷酸化的tau存在于前列腺癌细胞中，并且tau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来研究过度磷酸化的tau在控制细胞周期的信号转导机制中的功能。我们将验证tau通过与SFKs的相互作用增强AP-1介导的转录激活的假设，从而导致细胞增殖增加。具体目的是：(1)确定tau在癌细胞中调节AP-1活性的作用；(2)确定tau在抗癌药物应答中对细胞活力的影响。对抗癌药物的耐药性与乳腺癌中tau水平的升高有关，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断，从而导致耐药性。在这两个目的中，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，以及两种年龄相关疾病中细胞周期控制的丧失，我们的最终目的是确定过度磷酸化的tau蛋白是否能够打破细胞周期控制机制的平衡，从而促进细胞分裂。因此，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点是存在由异常形式的tau蛋白构成的脑损伤。这个应用程序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有相似之处。此外，癌细胞失去了对细胞周期的控制，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对细胞周期的控制。这个应用程序的数据将进一步加深我们对异常tau如何导致细胞死亡的理解。

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.