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Inhibition of Angiogenin enhanced rRNA Transcription

抑制血管生成素增强 rRNA 转录

基本信息

批准号：
6515043
负责人：
GUO-FU HU
金额：
$ 17.06万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-03-01 至 2003-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6515043
关键词：
RNA biosynthesis angiogenesis factor antisense nucleic acid breast neoplasms cell line cell nucleus cervix neoplasms colon neoplasms genetic transcription intracellular transport neomycin neoplasm /cancer pharmacology oligonucleotides prostate neoplasms ribosomal DNA ribosomal RNA

项目摘要

Sustained cell growth, a hallmark of cancer, requires continuous protein synthesis that depends on an adequate supply of ribosomes. Transcription of ribosomal RNA is a rate-limiting step in ribosome biosynthesis. Inhibition of ribosomal RNA transcription is therefore an effective means to decrease ribosomal biogenesis thereby inhibiting cell growth. Angiogenin, whose concentration is elevated in many cancers, has recently been found by our group to undergo nuclear translocation in actively proliferating cells where it binds to the promoter region of the ribosomal RNA gene and stimulates rRNA transcription. The nuclear function of angiogenin is confined to proliferating cells that would include cancer cells and some normal cells only under certain circumstances such as during development and wound healing. The purpose of this exploratory/development grant application is to determine whether or not angiogenin is involved in transcription of ribosomal RNA in cancer cells and whether or not inhibition of angiogenin-enhanced rRNA synthesis can serve as a new molecular target for cancer drug development. Experiments are designed (1) to examine the nuclear translocation profile of angiogenin in cancer cells thereby determining the differential behavior of angiogenin in cancer and normal cells; (2) to investigate angiogenin-enhanced rRNA synthesis in cancer cells and its relationship with nuclear accumulation of endogenous as well as exogenous angiogenin; and (3) to inhibit nuclear translocation of angiogenin in cancer cells and determine the effect of this inhibition on rRNA synthesis, growth rate, and cell proliferation. Results obtained would determine whether it is feasible to develop anticancer drugs based on the intervention of the nuclear function of angiogenin.

持续的细胞生长是癌症的标志，需要持续的蛋白质合成，这取决于核糖体的充足供应。核糖体RNA的转录是核糖体生物合成的限速步骤。因此，抑制核糖体RNA转录是减少核糖体生物合成从而抑制细胞生长的有效手段。血管生成素，其浓度在许多癌症中升高，最近被我们的小组发现在活跃增殖的细胞中进行核转位，在那里它结合到核糖体RNA基因的启动子区并刺激rRNA转录。血管生成素的核功能仅限于增殖细胞，包括癌细胞和某些正常细胞，仅在某些情况下，如在发育和伤口愈合期间。该探索性/开发资助申请的目的是确定血管生成素是否参与癌细胞中核糖体RNA的转录，以及抑制血管生成素增强的rRNA合成是否可以作为癌症药物开发的新分子靶点。设计实验（1）检测癌细胞中血管生成素的核转位谱，从而确定血管生成素在癌细胞和正常细胞中的差异行为;（2）研究血管生成素增强的癌细胞中rRNA合成及其与内源性和外源性血管生成素的核积累的关系;和（3）抑制癌细胞中血管生成素的核转位，并确定这种抑制对rRNA合成、生长速率和细胞增殖的影响。这些结果将决定是否可以通过干预血管生成素的核功能来开发抗肿瘤药物。