Systems genetics analyses predict a transcription role for P2P-R: molecular confirmation that P2P-R is a transcriptional co-repressor.
Systems genetics analyses predict a transcription role for P2P-R: molecular confirmation that P2P-R is a transcriptional co-repressor.
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系统遗传学分析预测 P2P-R 的转录作用：分子证实 P2P-R 是转录共阻遏物。
DOI：
10.1186/1752-0509-4-14
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发表时间：
2010-02-25
影响因子：
--
通讯作者：
Scott RE
中科院分区：
文献类型：
--
作者：
Peidis P;Giannakouros T;Burow ME;Williams RW;Scott RE
250 kDa P2P-R蛋白（也称为PACT和Rbbp 6）在十多年前被克隆，并被发现与p53和Rb 1肿瘤抑制蛋白结合。此外，P2P-R还与多种生物学功能相关，如有丝分裂、mRNA加工、翻译和泛素化。在目前的研究中，在线GeneNetwork系统被用来进一步探测P2P-R的生物学功能。然后进行分子研究以确认GeneNetwork的评估。基因网络和相关的基因本体链接被用来研究P2P-R与不同功能的基因集在脂肪细胞遗传参考面板的HXB/BXH重组品系的大鼠和眼睛遗传参考面板的BXD重组近交系小鼠的共表达。结果表明，包括P2P-R在内的75和135个转录相关基因产物的生物网络分别在大鼠脂肪细胞和小鼠眼睛中以遗传定义的方式共表达。在这一大组转录相关基因中，>10%与酶介导的转录相关。由于先前已报道P2P-R可结合SRC-1转录共调节因子（类固醇受体共激活因子1，[Ncoa 1]），因此评价了P2P-R对雌激素诱导的转录的可能影响。雌激素诱导的转录被抑制50-70%的瞬时转染P2P-R质粒构建成四种不同的细胞类型。此外，使用反义寡核苷酸敲低P2P-R表达增加雌激素介导的转录。免疫共沉淀实验证实P2P-R与SRC-1相互作用，也证实P2P-R与雌激素受体α相互作用。本研究中的发现为系统遗传学，特别是GeneNetwork在发现可通过分子分析证实的基因新功能方面的价值提供了强有力的支持。更具体地说，这些数据提供了证据表明，P2P-R的表达与大的转录网络以遗传学定义的方式共变，并且P2P-R可以作为雌激素依赖性转录的共阻遏物发挥作用。
The 250 kDa P2P-R protein (also known as PACT and Rbbp6) was cloned over a decade ago and was found to bind both the p53 and Rb1 tumor suppressor proteins. In addition, P2P-R has been associated with multiple biological functions, such as mitosis, mRNA processing, translation and ubiquitination. In the current studies, the online GeneNetwork system was employed to further probe P2P-R biological functions. Molecular studies were then performed to confirm the GeneNetwork evaluations. GeneNetwork and associated gene ontology links were used to investigate the coexpression of P2P-R with distinct functional sets of genes in an adipocyte genetic reference panel of HXB/BXH recombinant strains of rats and an eye genetic reference panel of BXD recombinant inbred strains of mice. The results establish that biological networks of 75 and 135 transcription-associated gene products that include P2P-R are co-expressed in a genetically-defined manner in rat adipocytes and in the mouse eye, respectively. Of this large set of transcription-associated genes, >10% are associated with hormone-mediated transcription. Since it has been previously reported that P2P-R can bind the SRC-1 transcription co-regulatory factor (steroid receptor co-activator 1, [Ncoa1]), the possible effects of P2P-R on estrogen-induced transcription were evaluated. Estrogen-induced transcription was repressed 50-70% by the transient transfection of P2P-R plasmid constructs into four different cell types. In addition, knockdown of P2P-R expression using an antisense oligonucleotide increased estrogen-mediated transcription. Co-immunoprecipitation assays confirmed that P2P-R interacts with SRC-1 and also demonstrated that P2P-R interacts with estrogen receptor α. The findings presented in this study provide strong support for the value of systems genetics, especially GeneNetwork, in discovering new functions of genes that can be confirmed by molecular analysis. More specifically, these data provide evidence that the expression of P2P-R co-varies in a genetically-defined manner with large transcription networks and that P2P-R can function as a co-repressor of estrogen-dependent transcription.
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作者：
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