Sp1, kappa-B enhancers and transcriptions in neurons

Sp1、kappa-B 增强子和神经元中的转录

• 批准号: 7340511
• 负责人: Steven W Barger
• 金额: $ 24.91万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-20 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340511
• 关键词: Binding; Biochemical; Biological Assay; Biological Sciences; Boron; Calcium; Calpain; Cathepsins; Cell Death; Cell Nucleus; Cell Survival; Cell physiology; Cells; Cerebral cortex; Cerebrum; Chromosome Pairing; Class; Complement; Complex; Condition; Cyclosporine; DNA; DNA Binding; Data; Elements; Endopeptidases; Enhancers; Event; Family member; Galactosidase; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Glutamate Receptor; Glutamates; Human; Infusion procedures; Ions; Laboratories; Learning; Light; Literature; Measures; Mediating; Memory; Mental Health; Molecular; NF-kappa B; NR1 gene; Nerve Degeneration; Nervous system structure; Neurons; Neurotoxins; Neurotransmitters; Nuclear Protein; Nuclear Proteins; Numbers; Peptide Hydrolases; Post-Translational Protein Processing; Process; Protein Binding; Proteins; Publishing; Receptor Activation; Relative (related person); Reporter; Reporting; Resistance; Role; Rubidium; Signal Transduction; Site; Speed; Staging; Stimulus; Stress; Synapses; Testing; Thinking; Toxic effect; Transfection; Transgenes; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Work; excitotoxicity; human NR1 protein; human TNF protein; human TYRP1 protein; inhibitor/antagonist; mutant; neuronal survival; neurotransmission; transcription factor

DESCRIPTION (provided by applicant): Infusion of the biological sciences with genetic sequencing of entire genomes has sped discovery, but complete utilization of this information awaits detailed information about gene regulation. Nowhere is this more apparent than in the nervous system, where environmental interactions with genetic information take the form of learning and memory. Glutamate is a paramount neurotransmitter in these processes, but also becomes a neurotoxin in several neurodegenerative conditions. Published literature suggests that activation of glutamate receptors can induce the transcription factor NF-kappa-B in CNS neurons; glutamatergic input has also been implicated in an apparent constitutive basal activity of NF-kappa-B in these cells. However, more stringent tests performed in support of this proposal indicate that glutamate does not activate NF-kappa-B DNA-binding in neurons cultured from the cerebral cortex. Furthermore, the only factors constitutively binding NF-kappa-B target sites are Sp1 and related proteins, and glutamate decreases this activity. Together, these results indicate that NF-kappa-B is not a glutamate-responsive transcription factor as previously thought. But considerable evidence still suggests that kappa-B elements control genes important for neuronal viability. The following hypothesis will be tested: Sp1-related proteins influence survival-promoting genes through binding to kappa-B elements, and glutamate toxicity involves a reduced binding of kappa-B elements by both Sp1 and NF-kappa-B. First, glutamate-evoked events that squelch NF-kappa-B activity in cortical neurons will be elucidated through tests of post-translational modifications and interactions with other proteins. Second, the role of NF-kappa-B in protection of neurons against glutamate toxicity will be examined. Third, mechanisms by which glutamate suppresses the activity of Sp1-related factors will be explored. Finally, the ability of Sp1-related proteins to control neuronal transcription through kappa-B cis elements, with particular regard to survival-promoting genes, will be explored. These studies should shed light on a contentious issue, namely, the role of NF-kappa-B and its DNA target sites in cerebral neurons. As such, this body of work could have direct impact on the mechanisms by which a major neurotransmitter impacts on the genetic correlates of memory, learning, and excitotoxic cell death, paradigms of considerable significance to human mental health.

描述（由申请人提供）：生物科学与整个基因组的基因测序的融合加速了发现，但该信息的完全利用还需要有关基因调控的详细信息。这一点在神经系统中最为明显，其中环境与遗传信息的相互作用表现为学习和记忆的形式。谷氨酸是这些过程中最重要的神经递质，但在几种神经退行性疾病中也成为神经毒素。已发表的文献表明，谷氨酸受体的激活可以诱导 CNS 神经元中的转录因子 NF-kappa-B；谷氨酸能输入也与这些细胞中 NF-κ-B 的明显基础活性有关。然而，为支持这一提议而进行的更严格的测试表明，谷氨酸不会激活从大脑皮层培养的神经元中的 NF-κ-B DNA 结合。此外，组成型结合 NF-κ-B 靶位点的唯一因素是 Sp1 和相关蛋白，而谷氨酸会降低这种活性。总之，这些结果表明 NF-kappa-B 并不像之前认为的那样是谷氨酸响应转录因子。但大量证据仍然表明 kappa-B 元件控制着对神经元活力至关重要的基因。将测试以下假设：Sp1 相关蛋白通过与 kappa-B 元件结合影响存活促进基因，而谷氨酸毒性涉及 Sp1 和 NF-kappa-B 与 kappa-B 元件的结合减少。首先，将通过翻译后修饰和与其他蛋白质相互作用的测试来阐明抑制皮质神经元中 NF-kappa-B 活性的谷氨酸诱发事件。其次，将检查 NF-κ-B 在保护神经元免受谷氨酸毒性中的作用。第三，将探讨谷氨酸抑制 Sp1 相关因子活性的机制。最后，将探讨 Sp1 相关蛋白通过 kappa-B 顺式元件控制神经元转录的能力，特别是生存促进基因。这些研究应该阐明一个有争议的问题，即 NF-κ-B 及其 DNA 靶位点在大脑神经元中的作用。因此，这项工作可能会对主要神经递质影响记忆、学习和兴奋性毒性细胞死亡的遗传相关性的机制产生直接影响，这些范式对人类心理健康具有相当重要的意义。