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

我们和其他人已经发现，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。我们已经表明，许多癌症，包括白血病，乳腺癌和结肠癌细胞核GH受体升高。如果我们人为地将GH受体靶向细胞核，那么当注射到免疫功能低下的小鼠中时，所产生的细胞是致瘤的，迅速形成转移性肿瘤。为了创造更有效的肿瘤发生抑制剂，并确定核GH受体的生理作用，我们将确定携带受体到细胞核并阻断它的转运过程，我们还将试图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-质谱法来鉴定在转运和基因激活过程中与受体相互作用的蛋白质。候选人的作用将通过阻止其表达或通过使用药物或显性阴性形式直接抑制其作用来测试。这些方法将为新的抗癌疗法和阻断糖尿病失明和肾衰竭的疗法提供线索。

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.