來自加拿大蒙特利爾臨床研究學(xué)院(Institut de recherches cliniques de Montreal, IRCM)的研究人員最近確定出控制炎癥的兩個(gè)至關(guān)重要的蛋白之間的相互作用,。這一重要的研究突破于近期發(fā)表在Molecular Cell期刊上,。
IRCM研究人員研究了糖皮質(zhì)激素(glucocorticoid)，其中糖皮質(zhì)激素是一類抑制免疫系統(tǒng)和減少炎癥的類固醇激素,。它們?cè)卺t(yī)學(xué)上被用來治療過敏癥,、哮喘和自身免疫疾病之類的疾病,。
IRCM分子遺傳學(xué)研究單位主任Jacques Drouin博士解釋道,，“在分子生物學(xué)和遺傳學(xué)上，被稱作轉(zhuǎn)錄因子的蛋白結(jié)合到DNA上以便控制遺傳信息的表達(dá)(或轉(zhuǎn)錄),。我們的研究定義出兩種轉(zhuǎn)錄因子---Stat3和糖皮質(zhì)激素受體(glucocorticoid receptor, GR)---在全基因組范圍內(nèi)的相互作用,。”
盡管Stat3作用于促炎癥性基因靶標(biāo)(pro-inflammatory gene target)，但是糖皮質(zhì)激素因它們的抗炎癥性質(zhì)和它們的受體GR與Stat3相互作用而被廣泛地用來控制這些作用,。GR能夠在體內(nèi)幾乎每個(gè)細(xì)胞內(nèi)被發(fā)現(xiàn),，并且能夠調(diào)節(jié)控制發(fā)育、代謝,、炎癥反應(yīng)和免疫反應(yīng)的基因,。
轉(zhuǎn)錄因子能夠單獨(dú)或者與其他蛋白控制信息流動(dòng)：通過促進(jìn)(作為激活劑)或阻斷(作為抑制劑)招募特異性基因表達(dá)所需的酶。轉(zhuǎn)錄因子能夠直接地結(jié)合到DNA上,，或者將它們自己附著到另一種DNA結(jié)合蛋白上,。
論文第一作者David Langlais說，“在某些情形下,，根據(jù)這些蛋白如何結(jié)合到DNA序列上,，它們將作出不同的表現(xiàn)。我們對(duì)理解為何一些轉(zhuǎn)錄因子能夠直接結(jié)合到DNA上而作為激活劑發(fā)揮作用以及當(dāng)它們被另一種蛋白招募而作為抑制劑發(fā)揮作用感到興趣,。迄今為止,，這種雙重作用的分子基礎(chǔ)一直還不清楚。”(生物谷：Bioon.com)
本文編譯自Controlling inflammatory and immune responses
doi:10.1016/j.molcel.2012.04.021
PMC:
PMID:
The Stat3/GR Interaction Code: Predictive Value of Direct/Indirect DNA Recruitment for Transcription Outcome
David Langlais, Catherine Couture, Aurélio Balsalobre, Jacques Drouin
Transcription factor recruitment to genomic sites of action is primarily due to direct protein:DNA interactions. The subsequent recruitment of coregulatory complexes leads to either transcriptional activation or repression. In contrast to this canonical scheme, some transcription factors, such as the glucocorticoid receptor (GR), behave as transcriptional repressors when recruited to target genes through protein tethering. We have investigated the genome-wide prevalence of tethering between GR and Stat3 and found nonreciprocal interactions, namely that GR tethering to DNA-bound Stat3 results in transcriptional repression, whereas Stat3 tethering to GR results in synergism. Further, other schemes of GR and Stat3 corecruitment to regulatory modules result in transcriptional synergism, including neighboring and composite binding sites. The results indicate extensive transcriptional interactions between Stat3 and GR; further, they provide a genome-wide assessment of transcriptional regulation by tethering and a molecular basis for integration of signals mediated by GR and Stats in health and disease.
