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The Role of A Transcription Cofactor in Tumorigenesis

转录辅因子在肿瘤发生中的作用

基本信息

批准号：
7339636
负责人：
HUA XIAO
金额：
$ 24.55万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-02-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7339636
关键词：
AF2 Affect Affinity Chromatography Age Amino Acid Substitution Apoptosis Biological Assay Breast Breast Cancer Model Breast Carcinoma CCND1 gene Cancer Patient Cathepsins Characteristics Complex Cyclin D1 DNA Data Development Diagnosis Ductal Carcinoma Ectopic Expression Engineering Epithelial Cells Estrogen Receptor alpha Estrogen Receptors Estrogens Event Exhibits Exons Gene Expression Regulation Gene Targeting Genes Genetic Transcription Growth HTATIP2 gene Human Incidence Intraductal Hyperplasia Intravenous Laboratories Lesion Liposomes Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary Tumorigenesis Mammary gland Mediating Molecular Mouse Mammary Tumor Virus Mus Mutant Strains Mice Mutation Neoplasm Metastasis Pathogenesis Play Predisposition Primary carcinoma of the liver cells Protein Overexpression Proteins Purpose Rate Regulation Regulatory Pathway Reporting Research Personnel Retroviridae Role SCID-hu Mice Sampling System Tamoxifen Techniques Testing Transcription Repressor/Corepressor Transcriptional Regulation Transgenes Transplantation Tumor Suppression Tumor Suppressor Proteins base c-myc Genes cancer cell carcinogenesis cell type chromatin immunoprecipitation cofactor human ESR1 protein in vivo insight malignant breast neoplasm melanoma neoplastic neoplastic cell outcome forecast programs promoter response tumor tumorigenesis v-H-ras Oncogene

项目摘要

DESCRIPTION (provided by applicant): Deregulation of c-Myc expression is implicated in pathogenesis of many human cancers including breast cancer. Estrogen receptor alpha can increase the rate of c-Myc transcription through the recruitment of a variety of cofactors to the c-Myc promoter, yet the precise roles of these cofactors in transcription and tumorigenesis are largely unknown. We have identified a putative tumor suppressor, TIP30, also called CC3, that can specifically regulate ER alpha-mediated c-Myc transcription. Our objective is to investigate the role of TIP30 in the regulation of transcription of ER alpha-target genes and tumorigenesis. The specific aims of this proposal are to: 1) investigate whether deletion of TIP30 increases expression of ER alpha-target genes in the epithelial cells of the mammary glands in vivo. 2) investigate whether breast cancers from patients harbor mutations in the TIP30 gene. 3) evaluate the susceptibility of TIP30-mutant mice to mammary tumorigenesis. These studies will have a significant impact on three important aspects. They will provide: 1) a molecular basis for a TIP30-mediated regulatory pathway in mammary gland development, 2) direct evidence for the role of a transcription cofactor in breast carcinogenesis, and 3) a system for studying biologically relevant factors and events responsible for the pathogenesis of breast cancers. Therefore, this proposal will not only yield insights into the mechanisms for regulation of gene expression intumorigenesis but also provide a potential target for the diagnosis and treatment of human cancers.

描述(申请人提供)：c-Myc表达的解除调控与包括乳腺癌在内的许多人类癌症的发病机制有关。雌激素受体α可以通过向c-Myc启动子募集多种辅因子来提高c-Myc的转录速率，但这些辅因子在转录和肿瘤发生中的确切作用在很大程度上还不清楚。我们已经确定了一个假定的肿瘤抑制因子TIP30，也称为CC3，它可以特异性地调节ERα介导的c-Myc转录。我们的目的是研究TIP30在ERα靶基因转录调控和肿瘤发生中的作用。本研究的目的是：1)研究TIP30基因缺失是否会增加乳腺上皮细胞ERα-靶基因的表达。2)调查乳腺癌患者是否存在TIP30基因突变。3)评价TIP30基因突变小鼠对乳腺肿瘤的易感性。这些研究将在三个重要方面产生重大影响。它们将提供：1)TIP30介导的乳腺发育调控途径的分子基础，2)转录辅助因子在乳腺癌发生中作用的直接证据，以及3)研究乳腺癌发病的生物学相关因素和事件的系统。因此，这一建议不仅将深入了解基因表达在肿瘤发生中的调控机制，而且将为人类癌症的诊断和治疗提供一个潜在的靶点。