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: 8939632
• 负责人: Chuxia Deng
• 金额: $ 93.03万
• 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/8939632
• 关键词: Affect; Aging; Biological Process; Breast; Carcinogens; Development; Diabetes Mellitus; Environment; Estrogens; Family; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Germ-Line Mutation; Gluconeogenesis; Glycolysis; Growth; Health; Histones; Human; Investigation; Knock-out; Knowledge; Laboratories; Link; Longevity; Malignant Neoplasms; Malignant neoplasm of ovary; Metabolism; Mutant Strains Mice; Mutation; Oncogenes; Pathway interactions; Play; Premature aging syndrome; Protein Isoforms; Proteins; Radiation; Role; Sirtuins; Stress; Syndrome; Testing; Triglycerides; base; cancer initiation; cancer prevention; drug testing; insulin sensitivity; interest; lipid metabolism; loss of function; malignant breast neoplasm; member; mouse model; prevent; transcription factor; tumor; tumor growth; tumor initiation; tumor metabolism; tumorigenesis

My laboratory has been investigating functions of the breast cancer associated gene 1 (BRCA1), p53, and Sirtuins in cancer, metabolism and aging. Germline mutations of BRCA1 are responsible for about 40% of cases of familiar human breast cancer. Mutations in BRCA1 are also responsible for 90% of cases of the combined familiar breast-ovarian cancer syndrome. Analyzing mouse models carrying various mutations, including isoform, null, point, hypomorphic and conditional knockout of BRCA1 generated by gene targeting, we have elucidated many of the fundamental mechanisms underlying BRCA1 associated tumorigenesis. We found that BRCA1-associated tumorigenesis is accompanied by massive genetic instability and p53 mutations, which markedly accelerates cancer initiation and growth. To illustrate the underlying mechanism, we demonstrated that BRCA1 plays an essential role in maintaining genome integrity; therefore BRCA1-deficiency alone does not cause tumor formation, instead, it triggers genetic instability, which eventually results in tumorigenesis after acquiring further permissive alterations, primarily p53 inactivation. These studies provided the first direct genetic evidence that p53 is involved in BRCA1-associated cancer. These mouse models are pivotal for the testing of drugs to prevent human cancers, and for testing the role of various agents, such as radiation, environment stress oncogenes, estrogens, and carcinogens in tumor initiation and growth. BRCA1 also positively regulates transcription of several members of the Sirtuin family, which serve as histone and protein deacetylases. We have generated and analyzed many Sirtuin mutant mice and found that loss of functions of SIRT1, 2, 3, and 4 results in tumorigenesis. Besides cancer, sirtuin mutant mice also displayed abnormalities in metabolic processes, including gluconeogenesis, glycolysis, fat metabolism, triglyceride synthesis, insulin sensitivity, diabetes, and/or premature aging. Thus, Sirtuins might serve as a link among cancer, aging and metabolism, which are potential interesting projects for investigation. Currently, we are investigating how the aging and metabolism affect the cancer development, how to increase health lifespan for cancer prevention, and how to effectively treat cancers based on our knowledge from studying BRCA1 and sirtuins.

我的实验室一直在研究乳腺癌相关基因1（BRCA1），p53和Sirtuins在癌症，代谢和衰老中的功能。 BRCA1的生殖线突变负责约40％的熟悉人类乳腺癌病例。 BRCA1中的突变也导致了90％的熟悉乳腺癌综合征的病例。分析携带各种突变的小鼠模型，包括基因靶向产生的BRCA1的同工型，无效，低形态和条件敲除，我们阐明了BRCA1相关肿瘤发生的许多基本机制。我们发现BRCA1相关的肿瘤发生伴随着巨大的遗传不稳定性和p53突变，这显着加速了癌症的启动和生长。为了说明潜在的机制，我们证明了BRCA1在维持基因组完整性中起着至关重要的作用。因此，仅BRCA1缺乏并不会引起肿瘤的形成，而是触发遗传不稳定，这在获得进一步的允许改变后最终导致肿瘤发生，主要是p53失活。这些研究提供了第一个直接的遗传证据，表明p53参与BRCA1相关癌症。这些小鼠模型对于预防人类癌症的药物测试以及测试各种药物的作用，例如辐射，环境应激癌基因，雌激素和癌在肿瘤启动和生长中的作用都是关键。 BRCA1还积极调节Sirtuin家族的几个成员的转录，这些家族用作组蛋白和蛋白质脱乙酰基酶。我们已经产生并分析了许多Sirtuin突变小鼠，发现SIRT1、2、3和4的功能丧失导致肿瘤发生。除癌症外，Sirtuin突变小鼠还显示出代谢过程中的异常，包括糖异生，糖酵解，脂肪代谢，甘油三酸酯合成，胰岛素敏感性，糖尿病和/或过早老化。因此，Sirtuins可能是癌症，衰老和代谢之间的联系，这是潜在的有趣项目。目前，我们正在研究衰老和代谢如何影响癌症的发展，如何根据我们研究BRCA1和SIRTUIN的知识来有效地治疗癌症的健康寿命以及如何有效治疗癌症。