基于PDB文件2grc并利用PyMQL渲染構(gòu)建蛋白BRG1的三維結(jié)構(gòu),，圖片來自維基共享資源,。
視黃酸(又稱維生素A)和類固醇是在我們身體中發(fā)現(xiàn)的激素，它們能夠讓我們身體免受氧化應(yīng)激(oxidative stress)帶來的傷害,，降低炎癥,，并參與細(xì)胞分化過程。腫瘤的特征之一就是它們的細(xì)胞喪失分化的能力,。因此這些激素?fù)碛凶柚拱┌Y發(fā)生的較好屬性,。當(dāng)前，視黃酸和類固醇也正被人們用來治療某些類型的白血病,。
來自西班牙Bellvitge生物醫(yī)學(xué)研究所(Bellvitge Biomedical Research Institute)的一個(gè)研究團(tuán)隊(duì)在EMBO Molecular Medicine期刊上發(fā)表一篇研究論文,，證實(shí)BRG1基因缺失導(dǎo)致癌細(xì)胞不再對這些激素作出反應(yīng)，因此腫瘤可能繼續(xù)生長,。
BRG1基因
Montse Sanchez-Cespedes領(lǐng)導(dǎo)的這個(gè)來自Bellvitge生物醫(yī)學(xué)研究所的研究團(tuán)隊(duì)在幾年前發(fā)現(xiàn)一個(gè)腫瘤抑制基因BRG1在非小細(xì)胞肺癌中因發(fā)生基因突變而失活,。“BRG1蛋白是調(diào)節(jié)幾個(gè)基因表達(dá)的染色質(zhì)重塑復(fù)合體(chromatin remodelling complex)的一部分”，Montse Sanchez-Cespedes解釋道,，“而且它與肺部細(xì)胞分化相關(guān),，允許細(xì)胞對某些激素(如維生素A或者類固醇等)作出反應(yīng)。”
當(dāng)BRG1基因發(fā)生突變而失活時(shí)，腫瘤細(xì)胞不再對這些激素作出反應(yīng),，因而它們繼續(xù)生長和擴(kuò)散,。因?yàn)檫@種原因，這些類型的腫瘤抵抗利用這些激素進(jìn)行的治療,。
臨床應(yīng)用
Montse Sanchez-Cespedes說,，“目前，我們不能恢復(fù)病人腫瘤抑制基因BRG1的功能,。因此,，我們?nèi)匀贿€不能將這一發(fā)現(xiàn)應(yīng)用于臨床治療，但是它使得我們更好地理解腫瘤的生物學(xué)特征,。在不久的未來,，我們將嘗試開展的研究就是尋找一些藥物試劑來特異性地破壞基因BRG1發(fā)生突變的細(xì)胞。” (生物谷：towersimper編譯)
doi:10.1002/emmm.201200236
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PMID:
The Tumor Suppressor and Chromatin Remodeling Factor BRG1 Antagonizes Myc Activity and Promotes Cell Differentiation in Human Cancer
Octavio A. Romero, Fernando Setien, Sam John, Pol Gimenez-Xavier, Gonzalo Gómez-López, David Pisano, Enric Condom, Alberto Villanueva, Gordon L. Hager, Montse Sanchez-Cespedes
BRG1, a member of the SWI/SNF complex, is mutated in cancer, but it is unclear how it promotes tumorigenesis. We report that re-expression of BRG1 in lung cancer cells up-regulates lung-specific transcripts, restoring the gene expression signature of normal lung. Using cell lines from several cancer types we found that those lacking BRG1 do not respond to retinoic acid (RA) or glucocorticoids (GC), while restoration of BRG1 restores sensitivity. Conversely, in SH-SY5Y cells, a paradigm of RA-dependent differentiation, abrogation of BRG1 prevented the response to RA. Further, our data suggest an antagonistic functional connection between BRG1 and MYC, whereby refractoriness to RA and GC by BRG1 inactivation involves deregulation of MYC activity. Mechanistically, some of these effects are mediated by BRG1 binding to MYC and MYC-target promoters. The BRG1-MYC antagonism was also evident in primary tumors. Finally, BRG1 restoration significantly dampened invasion and progression and decreased MYC in lung cancer cells orthotopically implanted in nude mice. Thus, BRG1 inactivation enables cancer cells to sustain undifferentiated gene expression programs and prevent its response to environmental stimuli.
