Bcl11b transcription factor regulation by phosphorylation and sumoylation

描述（由申请人提供）：细胞生长、成熟和转化等功能需要将细胞外信号翻译成改变的基因表达程序。这些信号的关键翻译者是转录因子蛋白。Bcl 11b是一种转录因子，对几个器官系统的发育和功能至关重要，包括免疫和中枢神经系统、皮肤和颅面结构。重要的是，Bcl 11b的失调与T细胞急性淋巴细胞白血病（T-ALL）（一种侵袭性儿童癌症）以及慢性髓细胞性白血病（CML）小鼠模型中致命急变期的加速密切相关。Bcl 11b缺失导致肿瘤进展的机制尚不清楚。此外，在发育或肿瘤转化中，细胞外信号冲击转录因子以调节转录组的方式也知之甚少。该实验室的长期目标是阐明信号转导途径调节转录因子活性的机制，目的是改变这种调节以治疗人类疾病。Bcl 11b通过激活胸腺细胞中的MAP激酶途径而被丰富地修饰，并且其活性依赖于刺激从基因阻遏物到激活物而变化。因此，Bcl 11b不仅与人类疾病有关，而且是研究亚分子结构变化与转录因子功能关系的极好模型。本研究的目的是识别Bcl 11b的翻译后修饰，并了解Bcl 11b的不同修饰状态与其不同活性之间的关系。对于这些研究，我们将使用先进的质谱技术，定点突变，过表达和敲低。在成功完成我们的具体目标后，我们将为其他寻求理解丰富修饰的转录因子的氨基酸水平修饰的时间组织的重要性的人提供方法学蓝图。我们的研究结果还应该强调潜在的分子靶点，以开发白血病和其他T细胞相关疾病的新疗法。我们还希望更好地了解Bcl 11 b在胸腺细胞成熟中的调节作用，并将我们的发现应用于其他器官系统。最后，我们将培养下一代的学生在21世纪世纪生物医学研究技术。 公共卫生相关性：我们希望最终了解如何操纵导致T细胞癌症和T细胞发育的基因表达变化。为此，我们正在研究Bcl 11b，这是免疫细胞和神经元中基因表达的重要调节因子。Bcl 11b在某些T细胞白血病中失调，缺乏Bcl 11b的小鼠具有不完整的免疫系统，缺乏成熟的T细胞以及其他缺陷。我们希望了解Bcl 11 b的活性是如何在T细胞的分子水平上控制的，从而开始了解其对基因表达的控制。

DESCRIPTION (provided by applicant): Cellular growth, maturation and transformation, among other functions, require the translation of extracellular signals into altered programs of gene expression. The key translators for these signals are transcription factor proteins. Bcl11b is a transcription factor that is critical for the development and function of several organ systems, including the immune and central nervous systems, skin, and craniofacial structures. Importantly, dysregulation of Bcl11b is strongly associated with T-cell acute lymphoblastic leukemia (T-ALL), an aggressive childhood cancer, and acceleration to the lethal blast crisis stage in a mouse model of chronic myelogenous leukemia (CML). The mechanism whereby loss of Bcl11b leads to tumor progression is not understood. In addition, the means by which extracellular signals impinge on transcriptional factors to regulate the transcriptome, in development or neoplastic transformation, is also poorly understood. The long-term goal of this laboratory is to elucidate the mechanisms by which signal transduction pathways regulate transcription factor activities with the goal of altering this regulation for treatment of human diseases. Bcl11b is richly modified by activation of the MAP kinase pathway in thymocytes, and its activity varies from gene repressor to activator dependent upon stimulation. Thus, Bcl11b not only has relevance to human disease, but is an excellent model to study the relationship between sub-molecular structural changes and transcription factor function. The goal of this proposal is to identify the stimulated, post-translation modifications of Bcl11b, and to understand the relationship between varying modified states of Bcl11b and its varied activities. For these studies we will use advanced mass spectrometry techniques, site-directed mutants, over expression and knockdown. Upon successful completion of our specific aims, we will provide a methodological blueprint for others seeking to understand the importance of the temporal organization of amino acid-level modifications of richly decorated transcription factors. Our findings should also highlight potential molecular targets for development of novel therapies in leukemia and perhaps other T cell-associated disorders. We also expect to better understand the regulation of Bcl11b in thymocyte maturation and to apply our findings to other organ systems. Finally, we will train a next generation of students in 21st century biomedical research techniques. PUBLIC HEALTH RELEVANCE: We wish to ultimately understand how to manipulate the gene expression changes leading to T cell cancers and in T cell development. To this end we are studying Bcl11b, an important regulator of gene expression in the immune cells and neurons. Bcl11b is dysregulated in certain T cell leukemia, and mice that lack Bcl11b have an incomplete immune system that lacks mature T cells among other defects. We wish to understand how the activity of Bcl11b is controlled at a molecular level in T cells to begin to understand its control of gene expression.