Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
Semin Cell Dev Biol. 2011 Sep;22(7):776-87. doi: 10.1016/j.semcdb.2011.07.024. Epub 2011 Aug 4.
Since the identification of a metazoan counterpart to yeast Mediator nearly 15 years ago, a convergent body of biochemical and molecular genetic studies have confirmed their structural and functional relationship as an integrative hub through which regulatory information conveyed by signal activated transcription factors is transduced to RNA polymerase II. Nonetheless, metazoan Mediator complexes have been shaped during evolution by substantive diversification and expansion in both the number and sequence of their constituent subunits, with important implications for the development of multicellular organisms. The appearance of unique interaction surfaces within metazoan Mediator complexes for transcription factors of diverse species-specific origins extended the role of Mediator to include an essential function in coupling developmentally coded signals with precise gene expression output sufficient to specify cell fate and function. The biological significance of Mediator in human development, suggested by genetic studies in lower metazoans, is emphatically illustrated by an expanding list of human pathologies linked to genetic variation or aberrant expression of its individual subunits. Here, we review our current body of knowledge concerning associations between individual Mediator subunits and specific pathological disorders. When established, molecular etiologies underlying genotype-phenotype correlations are addressed, and we anticipate that future progress in this critical area will help identify therapeutic targets across a range of human pathologies.
自 15 年前鉴定出酵母中介体的后生动物对应物以来，大量的生化和分子遗传学研究证实了它们作为一个整合中心的结构和功能关系，通过该中心，由信号激活的转录因子传递的调节信息被转导到 RNA 聚合酶 II。尽管如此，后生动物中介体复合物在进化过程中通过其组成亚基的数量和序列的实质性多样化和扩展而形成，这对多细胞生物的发育有重要影响。后生动物中介体复合物中独特的转录因子相互作用表面的出现，扩展了中介体的作用，包括将发育编码信号与精确的基因表达产物耦合的重要功能，足以指定细胞命运和功能。在较低等后生动物的遗传研究中，中介体在人类发育中的生物学意义得到了强调，大量与个体亚基的遗传变异或异常表达相关的人类病理列表突出了这一点。在这里，我们回顾了我们目前关于个体中介体亚基与特定病理紊乱之间关联的知识体系。当建立了基因型-表型相关性的分子病因时，我们预计这一关键领域的未来进展将有助于确定一系列人类病理的治疗靶点。
