糖皮質(zhì)激素受體(GR)是保守的核受體超家族中的一員，屬于核轉(zhuǎn)錄因子，其家族成員主要包括鹽皮質(zhì)激素受體、雄激素受體、甲狀腺激素受體、維生素D受體等多種受體，被激活后通過(guò)與核內(nèi)靶基因上的一段特定DNA序列結(jié)合從而調(diào)控基因的轉(zhuǎn)錄，發(fā)揮各種生物效應(yīng)。
GR先前已被證明在細(xì)胞發(fā)育、免疫反應(yīng)和代謝過(guò)程中發(fā)揮作用。它幾乎存在于人體內(nèi)的所有細(xì)胞中。許多廣泛使用的藥物，包括類固醇，都是通過(guò)這種蛋白質(zhì)而起作用。
四月六日，在美國(guó)國(guó)家科學(xué)院院刊《PNAS》發(fā)表的一項(xiàng)最新研究中，來(lái)自曼徹斯特大學(xué)的研究人員表明，當(dāng)科學(xué)家們減少GR表達(dá)之后，它發(fā)揮了一個(gè)新角色。延伸閱讀：Nature子刊：一種抑癌蛋白的新作用。
他們發(fā)現(xiàn)，缺乏GR的細(xì)胞，細(xì)胞分裂被打亂，染色體出現(xiàn)錯(cuò)誤。因?yàn)槿旧w錯(cuò)誤是癌癥的一個(gè)特征，他們減少GR在小鼠的表達(dá)，并觀察到，隨著年齡的增加，腫瘤有所增大。進(jìn)一步的分析表明，與周圍的正常組織相比，腫瘤組織具有更少的GR。
曼徹斯特大學(xué)人類發(fā)展研究所David Ray教授帶領(lǐng)了這項(xiàng)研究。他說(shuō)：“癌癥是由細(xì)胞分裂出錯(cuò)造成的，但沒(méi)有人曾探究GR在這個(gè)過(guò)程中發(fā)揮的作用。現(xiàn)在很清楚，它是至關(guān)重要的。”
他們研究了幾種常見(jiàn)的人類癌癥，包括前列腺癌、肺癌、肝癌、結(jié)腸癌和乳腺癌，發(fā)現(xiàn)在某些癌細(xì)胞類型中GR表達(dá)下降是一個(gè)共同特征，從而表明GR和腫瘤惡性進(jìn)展之間存在重要的關(guān)系，GR可能充當(dāng)一種腫瘤抑制基因。
本文第一作者Laura Matthews補(bǔ)充說(shuō)：“我們需要開(kāi)展更多的研究，但是這些這種新的機(jī)制，為我們了解‘癌癥是如何形成的’提供了更多見(jiàn)解，而有了這些知識(shí)，我們就能更有針對(duì)性地開(kāi)發(fā)新的治療方法，最終可能被用于人類。”
原文標(biāo)題：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. |
