Role of BRCA1 as a Human Tumor Suppressor Gene

BRCA1 作为人类肿瘤抑制基因的作用

• 批准号: 7278164
• 负责人: Eliot M. Rosen
• 金额: $ 25.02万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7278164
• 关键词: Adriamycin PFS; Aging; Antioxidants; Apoptosis; BRCA1 gene; BRCA2 gene; Base Sequence; Biological Process; Breast; Cancer Control; Cancer-Predisposing Gene; Cell Cycle Progression; Cell Death; Cells; Chromosomal Stability; Cultured Cells; DNA; DNA Damage; DNA Microarray Chip; DNA Microarray format; DNA Repair; DNA Topoisomerases; Defense Mechanisms; Development; Down-Regulation; EP300 gene; Embryo; Enzymes; Epithelial Cells; Estrogen Receptors; Exons; Experimental Animal Model; Fibroblasts; Figs - dietary; Functional disorder; Gene Expression; Genes; Genetic Recombination; Genome; Genome Stability; Genomics; Goals; Grant; HSPB1 gene; Heat shock proteins; Heat-Shock Response; Hereditary Malignant Neoplasm; Human; In Vitro; Inherited; Knowledge; Lead; Length; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Dysplasia; Mammary gland; Mediating; Methylation; Modeling; Molecular; Mus; Mutation; Nickel; Organ Culture Techniques; Oxidative Stress; Pathway interactions; Physiological; Play; Predisposition; Proteins; Proteome; Proteomics; Publishing; Rate; Receptor Signaling; Reduced Glutathione; Regulation; Research; Research Personnel; Risk; Role; Role playing therapy; Signal Transduction; Site; Small Interfering RNA; Source; Telomerase; Telomere Maintenance; Telomere Shortening; Testing; Tumor Suppressor Genes; Tumor Suppressor Proteins; attenuation; base; c-myc Genes; cancer cell; carcinogenesis; cell type; chemotherapy; functional loss; genetic regulatory protein; in vivo; inhibitor/antagonist; insight; loss of function; malignant breast neoplasm; novel; novel strategies; prevent; programs; promoter; repaired; response; telomere; transcription factor; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Background: Inherited mutations of the breast cancer susceptibility gene-1 (BRCA1) confer a high risk for breast cancer, ovarian cancer, and other tumor types. Accumulating evidence suggests that down-regulation or functional inactivation of BRCA1 plays a role in the development of sporadic (non-hereditary) cancers. BRCA1 plays roles in the regulation of cell cycle progression and DNA repair. However, the molecular bases for these roles are unclear, nor is it known if BRCA1 exerts other functions in cancer suppression. Preliminary Studies: During the initial grant period, we made great progress in understanding the molecular actions of BRCA1. We identified roles for BRCA1 in regulating the telomerase enzyme and telomere length and stability. We also demonstrated a role for BRCA1 in regulating the heat shock response and expression of a small heat shock protein, HSP27. We developed small interfering RNAs to non-toxically deplete BRCA1, allowing us to study the biological functions of endogenous BRCA1. We used DNA microarray analyses to identify novel BRCA1-regulated genes, including genes implicated in the antioxidant response; and we documented functional roles for BRCA1 in protecting cells against oxidative stress. Hypothesis: BRCA1 functions to preserve genomic and proteomic integrity via several distinct mechanisms that converge at common points: 1) stabilization of telomeres; and 2) stimulating antioxidant defenses. Conversely, loss of these functions promotes genomic/proteomic instability, leading to tumorigenesis. Research Aims: The major goals of this project are: SA1. To delineate the roles of BRCA1 in TERT regulation and telomere maintenance; SA2. To assess the mechanism(s) by which BRCA1 protects cells against oxidative stress in cultured cells; and SA3. To perform physiologic confirmatory studies on the role of BRCA1 in the antioxidant response in vivo in an experimental animal model. Significance: The focus of this competing continuation is to further elucidate the molecular function of BRCA1, particularly in mammary epithelial cell types. Using insights gained during the initial period, we will extend our knowledge of the molecular basis of the tumor suppressor activity of BRCA1. The roles of BRCA1 in telomere regulation and the antioxidant response also have implications for aging research. It is hoped that knowledge gained from these studies will lead to new approaches to cancer control and treatment.

描述（由申请人提供）： 背景：乳腺癌易感性基因1（BRCA1）的遗传突变赋予乳腺癌，卵巢癌和其他肿瘤类型的高风险。积累的证据表明，BRCA1的下调或功能失活在零星（非遗传性）癌症的发展中起作用。 BRCA1在调节细胞周期进程和DNA修复方面起着作用。但是，这些角色的分子碱基尚不清楚，也不知道BRCA1是否在癌症抑制中发挥了其他功能。 初步研究：在最初的赠款期间，我们在理解BRCA1的分子作用方面取得了巨大进展。我们确定了BRCA1在调节端粒酶和端粒长度和稳定性方面的作用。我们还证明了BRCA1在调节小热休克蛋白HSP27的热休克反应和表达中的作用。我们开发了小的干扰RNA，以非毒性耗尽的BRCA1，使我们能够研究内源性BRCA1的生物学功能。我们使用DNA微阵列分析来鉴定新型BRCA1调节的基因，包括与抗氧化反应有关的基因。我们记录了BRCA1在保护细胞免受氧化应激中的功能作用。 假设：BRCA1通过在共同点收敛的几种不同机制来保留基因组和蛋白质组学完整性：1）端粒的稳定； 2）刺激抗氧化剂防御。相反，这些功能的丧失会促进基因组/蛋白质组学不稳定性，从而导致肿瘤发生。 研究目的：该项目的主要目标是：SA1。描绘BRCA1在TERT监管和端粒维护中的作用； SA2。评估BRCA1保护细胞免受培养细胞中氧化应激免受氧化应激的机制；和SA3。对实验动物模型中BRCA1在体内的抗氧化反应中的作用进行生理验证研究。 意义：这种竞争延续的重点是进一步阐明BRCA1的分子功能，尤其是在乳腺上皮细胞类型中。使用在初期获得的见解，我们将扩展对BRCA1肿瘤抑制活性的分子基础的了解。 BRCA1在端粒调节和抗氧化反应中的作用也对衰老研究具有影响。希望从这些研究中获得的知识将导致癌症控制和治疗的新方法。