Bcl11b transcription factor regulation by phosphorylation and sumoylation

Bcl11b 转录因子通过磷酸化和苏酰化进行调节

• 批准号: 8036831
• 负责人: THERESA MARIE FILTZ
• 金额: $ 29.2万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8036831
• 关键词: Acceleration; Acute T Cell Leukemia; Amino Acids; Antibodies; Biological Models; Biomedical Research; Blast Phase; Cell Maturation; Cell physiology; Cells; Childhood Leukemia; Chronic Myeloid Leukemia; Code; Complex; Critical Pathways; Cultured Cells; Data; Defect; Detection; Development; Disease; Enzymes; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Transcription; Goals; Health; Human; Immune; Immune system; Innovative Therapy; Knock-out; Laboratories; Lead; Ligase; Link; MAP Kinase Activation Pathway; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Mature T-Lymphocyte; Methodology; Mitogen-Activated Protein Kinases; Modeling; Modification; Molecular; Molecular Target; Mus; Mutant Strains Mice; Neoplastic Cell Transformation; Neuraxis; Neurons; Pathologic Processes; Peptides; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Plasmids; Post-Translational Protein Processing; Protein Dephosphorylation; Proteins; Regulation; Regulator Genes; Research; Research Technics; Series; Signal Transduction; Signal Transduction Pathway; Site; Skin; Specificity; Staging; Structure; Students; Study models; System; T-Cell Development; T-Cell Leukemia; T-Lymphocyte; Techniques; Testing; Time; Tissues; Training; Transcription Coactivator; Translations; Ubiquitination; Work; adduct; base; body system; cell growth; cellular development; clinically relevant; craniofacial; extracellular; genetic regulatory protein; human disease; innovation; leukemia; mass spectrometer; molecular dynamics; mouse model; mutant; next generation; novel; progenitor; programs; promoter; prototype; thymocyte; transcription factor; tumor progression; ubiquitin ligase

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.

描述(由申请人提供)：细胞的生长、成熟和转化，以及其他功能，需要将细胞外信号转化为基因表达的改变程序。这些信号的关键翻译者是转录因子蛋白。Bcl11b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、皮肤和头面部结构。重要的是，Bcl11b的失调与T细胞急性淋巴细胞白血病(T-ALL)密切相关，T-ALL是一种侵袭性的儿童癌症，在慢性粒细胞白血病(CML)小鼠模型中加速到致命的原始细胞危象阶段。Bcl11b缺失导致肿瘤进展的机制尚不清楚。此外，在发育或肿瘤转化过程中，细胞外信号通过影响转录因子来调节转录组的方式也鲜为人知。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，目的是改变这一调节机制，用于治疗人类疾病。Bcl11b通过激活胸腺细胞中的MAPK通路而被大量修饰，其活性随刺激而从基因抑制子到激活子而变化。因此，Bcl11b不仅与人类疾病相关，而且是研究亚分子结构变化与转录因子功能关系的良好模型。这项建议的目的是确定Bcl11b的刺激和翻译后修饰，并了解Bcl11b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学技术、定点突变、过度表达和敲除。在成功完成我们的特定目标后，我们将为其他寻求了解修饰丰富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一份方法学蓝图。我们的发现还应该突出潜在的分子靶点，用于白血病和其他T细胞相关疾病的新疗法的开发。我们还希望更好地了解Bcl11b在胸腺细胞成熟中的调控，并将我们的发现应用于其他器官系统。最后，我们将培训下一代学生掌握21世纪的生物医学研究技术。 公共卫生相关性：我们希望最终了解如何操纵导致T细胞癌和T细胞发育的基因表达变化。为此，我们正在研究Bcl11b，它是免疫细胞和神经元中基因表达的重要调节因子。Bcl11b在某些T细胞白血病中调节失调，缺乏Bcl11b的小鼠免疫系统不完整，缺乏成熟的T细胞等缺陷。我们希望了解Bcl11b在T细胞中的活性是如何在分子水平上被控制的，从而开始了解它对基因表达的控制。