Mechanism of action of the v-erb A oncogene of AEV.

AEV 的 v-erb A 癌基因的作用机制。

基本信息

批准号：
7186526
负责人：
Martin L. Privalsky
金额：
$ 30.06万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-02-07 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7186526
关键词：
Accounting Acetylation Acute Acute Erythroblastic Leukemia Acute Promyelocytic Leukemia Adoption Affect Affinity Agonist Alkaline Phosphatase Alternative Splicing Amino Acid Receptors Amino Acid Sequence Amino Acid Substitution Amino Acids Anchorage-Independent Growth Antisense RNA Apoptosis Apoptotic Architecture Area Arsenic Arsenic Trioxide Avidity Belief Binding Binding Sites Biological Biological Process Birds Bone Marrow C-terminal Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Cataloging Catalogs Cell Nucleus Cells Chimera organism Chimeric Proteins Chromatin Chromosomal translocation Clinical Treatment Cloning Complement component C1s Condition Consensus Conventional (Clear Cell) Renal Cell Carcinoma Cultured Cells Cytoplasm DNA DNA Binding DNA Sequence Defect Derivation procedure Development Direct Repeats Disease Distant Dominant-Negative Mutation Endocrine Endocrine System Diseases Epidermal Growth Factor Receptor Erythroid Erythroid Cells Event Evolution Exhibits Family Feedback Fibroblasts Frequencies Funding Future Gagging Gene Expression Gene Targeting Generations Genes Genetic Genetic Transcription Genome Genomics Goals Grant Growth Growth Factor Growth Factor Receptors Hand Helix (Snails)Heterodimerization Homeostasis Homo Hormonal Hormone Receptor Hormones Human Hypothalamic structure In Vitro Incidence Inherited Intervention Investigation Laboratories Lead Lesion Leukemic Cell Leukocytes Ligands Link Liver MAP Kinase Modules Malignant Neoplasms Malignant neoplasm of liver Maps Mediating Messenger RNA Methodology Methods Mitogen-Activated Protein Kinases Mitogens Modeling Molecular Molecular Cloning Molecular Conformation Mutate Mutation Neoplasms Neurons Normal Cell Nuclear Nuclear Hormone Receptors Nuclear Receptors Numbers Oncogene Proteins Oncogenes Oncogenic Organism Orphan Pan Genus Pathogenicity Pathway interactions Pattern Peripheral Phenotype Phosphorylation Phosphorylation Site Phosphotransferases Physiology Pituitary Gland Play Positioning Attribute Primary carcinoma of the liver cells Principal Investigator Procedures Process Promega Property Protein Dephosphorylation Protein Isoforms Protein Kinase Proteins Protocols documentation Public Health Publications Publishing RNA Splicing RXR Range Recruitment Activity Refractory Regulation Regulatory Pathway Relative (related person)Reporter Reporting Repression Research Research Personnel Resistance Response Elements Retinoic Acid Receptor Retinoid Receptor Retroviridae Role Scotland Series Shrimp Signal Pathway Signal Transduction Signal Transduction Pathway Site Somatic Mutation Specific qualifier value Specificity Suggestion Surface Symptoms Synapses Syndrome Technology Testing Therapeutic Intervention Thinking Thyroid Hormone Receptor Thyroid Hormone Receptor Beta Thyroid Hormone Resistance Syndrome Thyroid Hormones Time Tissues Transcript Transcriptional Activation Transcriptional Regulation Transgenic Mice Translations Triiodothyronine Receptors Tumor Cell Line Tumor Suppressor Proteins Universities Variant Vertebrates Viral Vitamin D3 Receptor Work base calmodulin-dependent protein kinase IV cancer cell cancer risk cell type chromatin immunoprecipitation combinatorial concept dimer ear helix gene repression human NCOR1 protein human disease human tissue improved in vivo inhibitor/antagonist interest leukemia leukemogenesis mutant neoplastic neurochemistry non-oncogenic notch protein novel paralogous gene prevent progenitor programs promoter receptor receptor binding receptor function research study response retinoic acid receptor alpha transcription factor transcription factor PML tumor tumor initiation tumor progression tumorigenesis ward

项目摘要

We propose to better understand the mechanisms of action of the v-erb A oncogene, and to relate the role of v-erb A in viral neoplasia to events in normal differentiation and in human disease. V-erb A, an oncogene in the avian erythroblastosis retrovirus genome, participates in erythroid leukemogenesis and alters the growth properties of infected fibroblasts. V-erb A is a mutant, transduced copy of a normal cell gene (c-erb A) encoding a thyroid hormone receptor. Thyroid hormone receptors are ligand-regulated transcription factors, and belong to a larger family of nuclear receptors that play key roles in vertebrate development, homeostasis, and differentiation. Naturally occurring mutations in nuclear receptors have been implicated in important human endocrine and neoplastic diseases, including hepatocellular carcinoma, acute promyelocytic leukemia, renal clear cell carcinoma, and resistance to thyroid hormone syndrome. In many cases these mutant receptors, like v-Erb A, can act as dominant negatives. An important component of our research extends to understanding the molecular defects in these human diseases, and why different receptor mutations result in different diseases. We propose four specific aims to investigate these questions: SPECIFIC AIM A. We will identify v-Erb A and PML-RARalpha target genes. SPECIFIC AIM B. We will elucidate how v-Erb A represses target gene expression once bound to a target DMA SPECIFIC AIM C. We will elucidate how v-Erb A function is altered by other signal transduction pathways operative in the erythroleukemic cell SPECIFIC AIM D. We will use v-Erb A as a model to improve our understanding of the actions of the aberrant nuclear receptors involved in human disease. Relevance to public health: This research will help establish how alterations in normal genes can lead to cancers and other diseases. It will also contribute to our understanding of how hormone receptors function in normal physiology and development.

我们建议更好地了解 v-erb A 癌基因的作用机制，并将其作用联系起来病毒性肿瘤中的 v-erb A 与正常分化和人类疾病中的事件有关。 V-erb A，一种癌基因禽类成红细胞增多症逆转录病毒基因组，参与红系白血病发生并改变生长受感染的成纤维细胞的特性。 V-erb A 是正常细胞基因 (c-erb A) 的突变、转导副本编码甲状腺激素受体。甲状腺激素受体是配体调节的转录因子，属于一个更大的核受体家族，在脊椎动物发育中发挥关键作用，稳态和分化。核受体自然发生的突变与重要的人类内分泌和肿瘤疾病，包括肝细胞癌、急性早幼粒细胞白血病、肾透明细胞癌和甲状腺激素抵抗综合征。在许多在这种情况下，这些突变受体（如 v-Erb A）可以充当显性失活受体。我们的一个重要组成部分研究延伸到了解这些人类疾病的分子缺陷，以及为什么不同受体突变会导致不同的疾病。我们提出四个具体目标来研究这些问题：具体目标 A. 我们将鉴定 v-Erb A 和 PML-RARalpha 靶基因。具体目标 B. 我们将阐明 v-Erb A 在与靶标结合后如何抑制靶基因表达 DMA 具体目标 C. 我们将阐明其他信号转导途径如何改变 v-Erb A 功能在红白血病细胞中起作用具体目标 D. 我们将使用 v-Erb A 作为模型来提高我们对与人类疾病有关的异常核受体。与公共卫生的相关性：这项研究将有助于确定正常基因的改变如何导致癌症和其他疾病。它还将有助于我们了解激素受体如何发挥作用在正常的生理和发育中。