Inhibition of Angiogenin enhanced rRNA Transcription

细胞的持续生长是癌症的一个标志，它需要持续的蛋白质合成，这依赖于充足的核糖体供应。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。血管生成素在许多癌症中浓度升高，最近被我们的研究小组发现在活跃的增殖细胞中经历核转位，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，只有在某些情况下才会如此，例如在发育和伤口愈合期间。这项探索性/开发性拨款申请的目的是确定血管生成素是否参与癌细胞核糖体RNA的转录，以及抑制血管生成素增强的rRNA合成是否可以作为抗癌药物开发的新分子靶点。实验的目的是(1)检测癌细胞中血管生成素的核转位情况，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)研究血管生成素促进的癌细胞rRNA合成及其与内源性和外源性血管生成素核积聚的关系；以及(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、生长速度和细胞增殖的影响。这些结果将决定基于对血管生成素核功能的干预来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.