The nuclear growth hormone receptor- its actions and mechanism of nuclear translocation

核生长激素受体-其作用和核易位机制

• 批准号: nhmrc : 455864
• 负责人: Prof Michael Waters
• 金额: $ 35.45万
• 依托单位: The University of Queensland
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/nuclear-growth-hormone-nuclear-translocation/100056
• 关键词: nuclear; growth; hormone; receptor; its

We and others have found that cell surface receptors for growth factors such as EGF, FGF and growth hormone can be found in the nucleus of proliferating cells. We have shown that many cancers have elevated nuclear GH receptor including leukemia, breast and colon cancer. If we artificially target the GH receptor to the nucleus, the resulting cells are tumorigenic when injected into immunocompromised mice, rapidly form ing metastasising tumours. To create more effective inhibitors of this tumourogenesis, and to define the physiological roles of nuclear GH receptor, we will define the transport process which carries the receptor to the nucleus and block it. We will also seek to define how the receptor in the nucleus interacts directly with DNA to inhibit programmed cell death. To carry out these projects we will use sophisticated proteomics -mass spectrometry to identify the proteins interacting with the receptor in the transport and gene activation processes. The role of candidates will be tested by preventing their expression or by direct inhibition of their action using drugs or dominant negative versions. These approaches will provide leads to new anti-cancer therapeutics, and therapies for blocking diabetic blindness and kidney failure.

我们和其他人发现，生长因子（如 EGF、FGF 和生长激素）的细胞表面受体可以在增殖细胞的细胞核中找到。我们已经证明，许多癌症的核 GH 受体升高，包括白血病、乳腺癌和结肠癌。如果我们人为地将 GH 受体靶向细胞核，所产生的细胞在注射到免疫功能低下的小鼠体内时会产生致瘤性，迅速形成转移性肿瘤。为了创造更有效的肿瘤发生抑制剂，并定义核 GH 受体的生理作用，我们将定义将受体运送到细胞核并阻断它的转运过程。我们还将寻求确定细胞核中的受体如何直接与 DNA 相互作用以抑制程序性细胞死亡。为了开展这些项目，我们将使用复杂的蛋白质组学-质谱法来识别在运输和基因激活过程中与受体相互作用的蛋白质。候选者的作用将通过阻止其表达或使用药物或显性失活版本直接抑制其作用来测试。这些方法将为新的抗癌疗法以及阻止糖尿病失明和肾衰竭的疗法提供线索。