SNAG 抑制域在肿瘤发生中的功能-猫眼课题宝

SNAG 抑制域在肿瘤发生中的功能

批准号：

7214185

负责人：

FRANK JOSEPH RAUSCHER III

金额：

$30.49万

依托单位：

WISTAR INSTITUTE

依托单位国家：

美国

项目类别：

财政年份：

2003

资助国家：

美国

项目状态：

已结题

起止时间：

2003-04-01 至 2009-03-31

来源：

https://reporter.nih.gov/project-details/7214185

关键词：

Amino Acids Antibodies Azacitidine BAK1 gene BAX gene BTB/POZ Domain Bax protein Binding Biological Biological Assay Biological Process CDKN1A gene Cell Death Cell Fractionation Cell Nucleus Cell Proliferation Cells Characteristics Chromatin Chromatography Co-Immunoprecipitations Complex Cytoplasm DNA Binding DNA Binding Domain DNA Methylation DNA Restriction Enzymes Deoxyribonuclease I Development Dominant-Negative Mutation Embryonal Carcinoma Cell End Point Epitopes Family G1 Arrest Gel Gene Targeting Genes Glutathione S-Transferase Growth Growth Factor Growth Factor Oncogenes Histones IL2 gene In Vitro Interleukin-2 Kinetics LIM Domain LIM Domain Protein Length Localized Maps Mass Spectrum Analysis Mediating Modification Molecular Monitor Mutation Nuclear Nuclear Receptors Pathway interactions Personal Satisfaction Point Mutation Population Property Proteins RNA Interference Reagent Regulation Repression Role Scheme Signal Transduction Snails Specificity Structure System T-Cell Development T-Lymphocyte Thymoma Transgenic Model Tretinoin Trichostatin A Vertebrates Western Blotting Withdrawal Yeasts ZYX gene Zinc Fingers base chromatin immunoprecipitation gene repression human ZNF45 protein in vivo kinase inhibitor mutant novel oncoprotein p21 polypeptide promoter protein expression protein protein interaction prototype reconstitution research study scaffold tumorigenesis yeast two hybrid system

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DESCRIPTION (provided by applicant): The Snail-GFI1 (SNAG) subfamily of eukaryotic zinc finger (ZF) proteins encodes key regulators of developmental and homeostatic pathways in metazoans. The SNAG-ZF family in vertebrates share a COOH-terminal DNA binding domain composed of 5 -7 Cys2-His2 zinc fingers and a highly conserved NH2- terminus which contains the 21 amino acid SNAG repression domain. This domain is a potent, transferable repression domain. Nothing is known about the mechanisms of SNAG domain-mediated repression. The prototype SNAG domain-containing oncogene, GFI1 (growth-factor independence-1) is responsible for development of T-cell thymomas. We used the GFI1 SNAG domain and first performed a comprehensive mutagenic analysis of SNAG-mediated repression and used this set of mutations to distinguish candidate SNAG-corepressor proteins in a yeast two hybrid screen. We discovered a novel, LIM domain containing protein AJUBA which binds to wild-type SNAG domain but not to mutants which lack repression activity. The SNAG-AJUBA interaction occurs in vivo and enhances SNAG domain mediated repression. Remarkably, the AJUBA protein shuttles between the cytoplasm and the nucleus and may represent a novel signaling system which utilizes the SNAG repression domain as the nuclear receptor. We will further characterize the GFI1-AJUBA interaction by performing the following specific aims: Specifically we will: 1. Identify and characterize an endogenous GFI1-AJUBA complex, reconstitute, map and determine the specificity of the SNAG domain-AJUBA interaction in vitro and in vivo. 2. Define the mechanism of GFI1-AJUBA mediated repression, the molecular characteristics of the repressed locus and the influence of Ras signaling on AJUBA co-repression. 3. Define the biological relevance of SNAG domain-AJUBA interactions using in vivo cell proliferation and differentiation systems which are dependent upon SNAG-ZFs and AJUBA function. 4. Purify an endogenous GFI1 and AJUBA complex and define the components and their regulation.

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