糖皮质激素受体(GR)是保守的核受体超家族中的一员，属于核转录因子，其家族成员主要包括盐皮质激素受体、雄激素受体、甲状腺激素受体、维生素D受体等多种受体，被激活后通过与核内靶基因上的一段特定DNA序列结合从而调控基因的转录，发挥各种生物效应。
GR先前已被证明在细胞发育、免疫反应和代谢过程中发挥作用。它几乎存在于人体内的所有细胞中。许多广泛使用的药物，包括类固醇，都是通过这种蛋白质而起作用。
四月六日，在美国国家科学院院刊《PNAS》发表的一项最新研究中，来自曼彻斯特大学的研究人员表明，当科学家们减少GR表达之后，它发挥了一个新角色。延伸阅读：Nature子刊：一种抑癌蛋白的新作用。
他们发现，缺乏GR的细胞，细胞分裂被打乱，染色体出现错误。因为染色体错误是癌症的一个特征，他们减少GR在小鼠的表达，并观察到，随着年龄的增加，肿瘤有所增大。进一步的分析表明，与周围的正常组织相比，肿瘤组织具有更少的GR。
曼彻斯特大学人类发展研究所David Ray教授带领了这项研究。他说：“癌症是由细胞分裂出错造成的，但没有人曾探究GR在这个过程中发挥的作用。现在很清楚，它是至关重要的。”
他们研究了几种常见的人类癌症，包括前列腺癌、肺癌、肝癌、结肠癌和乳腺癌，发现在某些癌细胞类型中GR表达下降是一个共同特征，从而表明GR和肿瘤恶性进展之间存在重要的关系，GR可能充当一种肿瘤抑制基因。
本文第一作者Laura Matthews补充说：“我们需要开展更多的研究，但是这些这种新的机制，为我们了解‘癌症是如何形成的’提供了更多见解，而有了这些知识，我们就能更有针对性地开发新的治疗方法，最终可能被用于人类。”
原文标题：Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy
原文摘要：Abstract：The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily, which controls programs regulating cell proliferation, differentiation, and apoptosis. We have identified an unexpected role for GR in mitosis. We discovered that specifically modified GR species accumulate at the mitotic spindle during mitosis in a distribution that overlaps with Aurora kinases. We found that Aurora A was required to mediate mitosis-driven GR phosphorylation, but not recruitment of GR to the spindle. GR was necessary for mitotic progression, with increased time to complete mitosis, frequency of mitotic aberrations, and death in mitosis observed following GR knockdown. Complementation studies revealed an essential role for the GR ligand-binding domain, but no clear requirement for ligand binding in regulating chromosome segregation. The GR N-terminal domain, and specifically phosphosites S203 and S211, were not required. Reduced GRexpression results in a cell cycle phenotype, with isolated cells from mouse and human subjects showing changes in chromosome content over prolonged passage. Furthermore, GR haploinsufficient mice have an increased incidence of tumor formation, and, strikingly, these tumors are further depleted for GR, implying additional GR loss as a consequence of cell transformation. We identified reduced GR expression in a panel of human liver, lung, prostate, colon, and breast cancers. We therefore reveal an unexpected role for the GR in promoting accurate chromosome segregation during mitosis, which is causally linked to tumorigenesis, making GR an authentic tumor suppressor gene. |
