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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：
10447120
负责人：
JIANDONG CHEN
金额：
$ 31.95万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447120
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 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.

蛋白质紊乱对转录激活的调节