INHIBITION OF BREAST TUMORIGENICITY BY C MYC PO RNA

C MYC PO RNA 对乳腺肿瘤发生的抑制作用

• 批准号: 6514644
• 负责人: SCOTT W BLUME
• 金额: $ 10.76万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514644
• 关键词: SCID mouse; breast neoplasms; cell proliferation; gene induction /repression; genetic promoter element; messenger RNA; metastasis; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic growth; protooncogene; tissue /cell culture; transcription factor

DESCRIPTION: (Applicant's Description) The po transcript of the human c-myc gene is initiated over 600 bp upstream of the major Pl/P2 start sites, and its sequence corresponds to regulatory regions of the core promoter DNA. We hypothesize that this 5'-untranslated RNA sequence is a fundamental participant in the transcriptional regulation of c-myc and the ultimate determination of cellular phenotype. In preliminary experiments, we have determined that the PO RNA is capable of binding specific DNA sequences within the core Pl promoter and the first exon of c-myc. Furthermore, we have found that enforced expression of the sequence unique to the po transcript is associated with drastic, alterations in phenotype of malignant cells, including greater than 90 percents decrease in anchorage- independent growth in soft agar, and complete loss of the ability to form tumors in I immunodeficient mice. We propose to explore the potential therapeutic utility of this RNA sequence for modulating c-myc expression and interfering with proliferation, invasion, and metastasis of human breast cancer cells. The Specific Aims are: 1. Investigate the potential of the 5'-untranslated RNA sequence of the human c-myc PO transcript to regulate c-myc expression, by interacting with and blocking access to particular segments of the promoter / template DNA, or by specifically recruiting /sequestering individual polypeptide transcription factors. 2. Enforcibly express the 5'-untranslated sequence of the c-myc PO transcript in malignant and nontransformed human breast cells, to evaluate the potential therapeutic utility of this natural RNA sequence for modulating the proliferative and invasive capacity of the malignant cells. 3. Assess the degree to which artificial manipulation of the PO 5'-untranslated sequence alters the inherent tumorigenic, invasive, and metastatic potential of human breast carcinoma xenografts in immunocompromised mice.

描述：（申请人的描述） 人类C-MYC基因的PO转录本始于上游600 bp以上 主要的PL/P2启动位点，其序列对应于调节 核心启动子DNA的区域。 我们假设这5'-无翻译 RNA序列是对转录调控的基本参与者 C-MYC和细胞表型的最终确定。 在初步 实验，我们已经确定PO RNA能够结合特定 核PL启动子和C-Myc的第一个外显子内的DNA序列。 此外，我们发现强制执行该序列的表达 PO转录本与急剧的变化有关 恶性细胞，包括大于90个per量的锚定细胞 - 软琼脂的独立增长，并完全丧失形成的能力 I免疫缺陷小鼠中的肿瘤。我们建议探索潜力 该RNA序列调节C-MYC表达和 干扰人类乳房的扩散，侵袭和转移 癌细胞。具体目的是：1。调查 人类C-MYC PO转录本的5'-非翻译RNA序列调节 C-MYC表达，通过与特定的互动并阻止访问 启动子 /模板DNA的片段，或通过专门募集 /隔离单个多肽转录因子。 2。强行 在恶性肿瘤中表达C-MYC PO转录本的5'-非翻译序列 和未转化的人类乳腺细胞，以评估潜在的治疗性 这种天然RNA序列的效用，用于调节增生性和 恶性细胞的侵入性能力。 3。评估程度 PO 5'-非翻译序列的人工操纵改变了固有的 人类乳腺癌的致瘤，侵入性和转移性潜力 免疫功能低下的小鼠中的异种移植物。