Inhibition of Angiogenin enhanced rRNA Transcription

持续的细胞生长是癌症的一个标志，它需要持续的蛋白质合成，这依赖于核糖体的充足供应。核糖体RNA的转录是核糖体生物合成中的一个限速步骤。因此，抑制核糖体RNA转录是减少核糖体生物发生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发生核易位，在那里它与核糖体RNA基因的启动子区域结合并刺激rRNA转录。血管生成素的核功能仅限于增殖细胞，包括癌细胞和一些正常细胞，只有在某些情况下，如在发育和伤口愈合过程中。这项探索性/开发性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。实验设计(1)检查肿瘤细胞中血管生成素的核易位谱，从而确定肿瘤细胞和正常细胞中血管生成素的不同行为；(2)研究肿瘤细胞中血管生成素增强的rRNA合成及其与内源性和外源性血管生成素核积累的关系；(3)抑制肿瘤细胞中血管生成素的核易位，并确定这种抑制对rRNA合成、生长速度和细胞增殖的影响。研究结果将决定在干预血管生成素核功能的基础上开发抗癌药物是否可行。

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.