Regulation of transcriptional activation by protein disorder

蛋白质紊乱对转录激活的调节

基本信息

批准号：
10654659
负责人：
JIANDONG CHEN
金额：
$ 32.02万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654659
关键词：
Affinity Apoptotic Architecture Binding Binding Sites Biophysics Burial Cell Cycle Cell Proliferation Cell Survival Cells Cellular Stress Chimera organism Clinic Complex Coupling DNA DNA Binding DNA Binding Domain DNA Damage Development Disease Electrostatics FDA approved Gene Activation Gene Expression Genes Genetic Transcription Goals Homologous Gene Hydrophobic Surfaces In Vitro Malignant Neoplasms Measures Mediating Molecular Biology Mutate N-terminal Neoplasm Metastasis Normal tissue morphology Nucleic Acids Oncogenic Pharmaceutical Preparations Phosphorylation Play Property Regulation Research Role Sequence-Specific DNA Binding Protein Solid Neoplasm Specificity TP53 gene Toxicity due to chemotherapy Transactivation Transcriptional Activation Transcriptional Regulation Tumor Suppressor Proteins cancer therapy design experimental study improved in vivo intermolecular interaction mimicry mutant promoter protein activation response small molecule targeted cancer therapy transcription factor ubiquitin-protein ligase

项目摘要

Regulation of transcriptional activation by protein disorder PIs: Daughdrill/Chen Abstract The p53 tumor suppressor is a sequence-specific DNA binding protein that activates gene transcription to regulate cell survival and proliferation. It is mutated in at least 50% of solid tumors and some of these mutants are oncogenic and activate the transcription of genes that promote cell survival and metastasis. Despite decades of research on p53, there are currently no FDA approved drugs in the clinic that directly target wt or mutant p53. This is, in part, because 50% of p53 is disordered and we have an incomplete understanding of what these regions look like and how they function. We have recently shown that the disordered N-terminal acidic transactivation domain of p53 (NT) dynamically interacts with the DNA binding domain (DBD) with residues that contact DNA. This interaction inhibits DNA binding but increases binding specificity using a combination of nucleic acid mimicry and electrostatic shielding that enhances recognition of promoter binding sites in vivo. We propose to: (1) Determine the specific effects of nucleic acid mimicry and electrostatic shielding on DNA binding specificity, and how tethering controls the intramolecular interaction between NT and DBD. (2) Investigate how p53 NT phosphorylation regulates DNA binding affinity and specificity to create adaptable switching of transcriptional activation. (3) Determine how MdmX interferes with p53 DNA binding when it forms a heterodimer with p53. Successful completion of these experiments will lead to a better understanding of how p53 governs cell fate after DNA damage by regulating the binding specificity to pro-survival versus pro-apoptotic target genes. A deeper understanding of the structural and functional properties of the weak dynamic interactions within p53 and between p53 and MdmX is necessary for the successful development of small molecules to target these interactions for cancer therapy.

调节蛋白质障碍的转录激活 PIS：Daughdrill/Chen 抽象的 p53肿瘤抑制剂是一种激活基因转录的序列特异性DNA结合蛋白调节细胞存活和增殖。它在至少50％的实体瘤中突变，其中一些是突变体是致癌的，并激活了促进细胞存活和转移的基因的转录。尽管对p53进行了数十年的研究，但目前诊所中没有FDA批准的药物直接靶WT或突变体P53。这部分是因为50％的p53是无序的，我们有一个不完整的了解这些区域的外观及其功能。我们最近表明 p53（NT）的N端酸性反式激活结构域与DNA动态相互作用结合域（DBD）与接触DNA的残基。这种相互作用抑制了DNA的结合，但使用核酸模仿和静电屏蔽的结合来提高结合特异性增强对体内启动子结合位点的识别。我们建议：（1）确定特定效果 DNA结合特异性上的核酸模仿和静电屏蔽，以及束缚如何控制 NT和DBD之间的分子内相互作用。（2）研究p53 nt磷酸化如何调节DNA结合亲和力和特异性以创建转录激活的适应性切换。（3）确定MDMX在与p53形成异二聚体时如何干扰p53 DNA结合。这些实验的成功完成将使人们更好地了解p53如何控制细胞 DNA损伤后的命运，通过调节与临床的结合特异性与促凋亡靶标的结合。基因。对弱动态的结构和功能特性有更深入的了解 p53和p53和mdmx之间的相互作用对于成功发展是必要的小分子以这些相互作用进行癌症治疗。