THE PML-RAR ONCOGENIC FUSION PROTEIN AND ITS ROLE IN ACUTE PROMYELOCYTIC LEUKEMI

PML-RAR 致癌融合蛋白及其在急性早幼粒细胞白血病中的作用

• 批准号: 7610048
• 负责人: CHRISTOPHER S FRANCKLYN
• 金额: $ 1.32万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610048
• 关键词: Acute; Acute Promyelocytic Leukemia; Affect; Binding; Biological Assay; Cell Line; Chimeric Proteins; Chromosomes, Human, Pair 15; Computer Retrieval of Information on Scientific Projects Database; Dissociation; Energy Transfer; Fluorescence Anisotropy; Funding; Genetic Transcription; Grant; Institution; Ligand Binding Domain; Mutation; Myelogenous; Nuclear; Oncogene Proteins; Oncogenic; PML gene; Patients; Peptides; Play; Proteins; Reciprocal Translocation; Relapse; Research; Research Personnel; Resistance; Resources; Retinoic Acid Binding; Retinoic Acid Receptor; Role; Signal Transduction; Source; Tretinoin; Tumor Suppressor Proteins; United States National Institutes of Health; base; cofactor; mutant

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Acute Promyelocytic Leukemia (APL) results from a specific reciprocal translocation between chromosomes 15 and 17. The translocation fuses the genes for the PML tumor suppressor and retinoic acid receptor a (RARa), generating a PML-RARa chimeric oncoprotein that interferes with signaling associated with myeloid differentiation. APL patients receive treatment with all-trans retinoic acid (ATRA), but invariably undergo relapse owing to mutations imparting ATRA resistance in the ligand binding domain (LBD) of the RARa portion of the fusion protein. The mutations affect the ability of the protein to bind retinoic acid, as well as undergo release and binding of nuclear co-repressor (N-CoR) and co-activator (ACTR) proteins, respectively. These cofactors play essential roles in RARa transcription function. We developed fluorescence anisotropy and resonance energy transfer assays to quantitate the binding of coactivator and corepressor peptides to the wild-type RARa LBD and four ATRA resistant mutants in the presence of varying concentrations of ATRA. By use of these assays, we have determined cofactor dissociation constants and defined the basis of ATRA resistance in these patient and cell line mutations in terms of cofactor recruitment.

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