Roles of BRCA1 transcription target genes in tumorigenesis and aging

BRCA1转录靶基因在肿瘤发生和衰老中的作用

• 批准号: 7967612
• 负责人: Chuxia Deng
• 金额: $ 43.63万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7967612
• 关键词: Acute; Age; Aging; Alleles; Atrophic condition of skin; Biological Process; Body fat; Cells; Chromatin; DNA Microarray Chip; Data; Defect; Deposition; Deterioration; Early Diagnosis; Early identification; Epigenetic Process; Exhibits; Fertility; Gene Targeting; Genes; Genetic; Genetic Transcription; Histone H3; Histone H4; Human; IGF-1 Signaling Pathway; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Receptor; Length; Longevity; Mammary Neoplasms; Modification; Molecular; Mus; Mutant Strains Mice; Organism; Osteoporosis; Pathway interactions; Phenotype; Physiological; Play; Premature aging syndrome; RNA Interference; Role; Signal Transduction; Symptoms; System; TP53 gene; Therapeutic; Wound Healing; age related; base; cell growth; gene repression; insight; malignant breast neoplasm; member; mutant; neoplastic cell; null mutation; promoter; transcription factor; tumorigenesis

Recently, we have shown that mice, which are homozygous for a targeted deletion of the full-length Brca1, and heterozygous for p53-null mutation (Brca111/11p53+/) exhibit premature aging characterized by decreased life span, reduced body fat deposition, osteoporosis, skin atrophy, and decreased wound healing. The Brca111/11p53+/ mice also suffer increased tumorigenesis when the remaining wild-type (WT) p53 allele is lost. The molecular mechanisms underlying these defects are not clear. Using DNA microarray and candidate approaches, we have identified over 100 genes that are differentially expressed in BRCA1 mutant and control cells. Analyzing and validating these genes based on phenotypes of mutant mice and cells may allow the identification of earliest changes associated with tumorigenesis, and markers for early diagnosis of mammary tumors. Aging has been defined in humans as the age-related deterioration of physiologic functions necessary for the survival and fertility of an organism. Multiple environmental- and/or genetic-related factors, including, Sir2, and insulin-like growth factor-1 (IGF-I) signaling, have been associated with various aging symptoms. In the past year, we have focused on interactions between BRCA1 and the IGF-1 signaling pathway for tumorigenesis and aging. Our data indicate that Brca1 deficiency leads to increased expression of several IGF signaling axis members (i.e. IGF-1, IGF receptor-1, and IRS-1) in multiple experimental systems, including BRCA1-deficient mice, primary mammary tumors, and cultured human cells. Furthermore, we provide evidence that activation of IGF signaling by BRCA1 deficiency can also occur in a p53-independent fashion. Our data indicate that BRCA1 interacts with the IRS-1 promoter and inhibits its activity that is associated with epigenetic modification of histone H3 and histone H4 to a transcriptional repression chromatin configuration. We further show that BRCA1-deficient mammary tumor cells exhibit high levels of IRS-1, and acute suppression of Irs-1 using RNA interference significantly inhibits growth of these cells. Those observations provide a molecular insight in understanding both fundamental and therapeutic BRCA1-associated tumorigenesis and aging.

最近，我们已经表明，对于全长BRCA1的靶向缺失而纯合的小鼠，以及用于p53-null突变（BRCA111/11P53+/）的杂合子表现出早熟的过早衰老，其特征是寿命减少，体内脂肪沉积减少，骨质骨质病，骨质病，骨质症，伤口疗养和减少。当剩余的野生型（WT）p53等位基因丢失时，BRCA111/ 11P53+/小鼠的肿瘤发生也增加。这些缺陷背后的分子机制尚不清楚。使用DNA微阵列和候选方法，我们已经确定了在BRCA1突变体和对照细胞中差异表达的100多种基因。根据突变小鼠和细胞的表型分析和验证这些基因可能允许鉴定与肿瘤发生相关的最早变化，以及用于早期诊断乳腺肿瘤的标志物。 衰老已被定义为人类与年龄相关的生理功能的恶化，这是生物体生存和生育能力所必需的。多种环境和/或遗传相关因素，包括SIR2和胰岛素样生长因子1（IGF-I）信号传导，与各种衰老症状有关。在过去的一年中，我们专注于BRCA1与肿瘤发生和衰老的IGF-1信号传导途径之间的相互作用。我们的数据表明，BRCA1缺乏导致多个实验系统中的几个IGF信号轴成员（即IGF-1，IGF受体1和IRS-1）的表达增加，包括BRCA1缺陷型小鼠，原发性乳腺肿瘤和培养的人类细胞。此外，我们提供的证据表明，BRCA1缺乏症对IGF信号的激活也可以以p53独立的方式发生。我们的数据表明，BRCA1与IRS-1启动子相互作用，并抑制与组蛋白H3和组蛋白H4的表观遗传修饰与转录抑制染色质构型相关的活性。我们进一步表明，BRCA1缺陷型乳腺肿瘤细胞表现出高水平的IRS-1，并且使用RNA干扰对IRS-1的急性抑制显着抑制了这些细胞的生长。这些观察结果为理解基本和治疗性BRCA1相关的肿瘤发生和衰老提供了分子见解。