Department of Orthopaedics, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo, Kyoto 606-8507, Japan.
J Bone Miner Metab. 2011 Jul;29(4):390-5. doi: 10.1007/s00774-011-0273-9. Epub 2011 May 19.
Since the discovery of SOX9 mutations in the severe human skeletal malformation syndrome campomelic dysplasia in 1994, Sox9 was shown to be both required and sufficient for chondrocyte specification and differentiation. At the same time, its distant relatives Sox5 and Sox6 were shown to act in redundancy with each other to robustly enhance its functions. The Sox trio is currently best known for its ability to activate the genes for cartilage-specific extracellular matrix components. Sox9 and Sox5/6 homodimerize through domains adjacent to their Sry-related high-mobility-group DNA-binding domain to increase the efficiency of their cooperative binding to chondrocyte-specific enhancers. Sox9 possesses a potent transactivation domain and thereby recruits diverse transcriptional co-activators, histone-modifying enzymes, subunits of the mediator complex, and components of the general transcriptional machinery, such as CBP/p300, Med12, Med25, and Wwp2. This information helps us begin to unravel the mechanisms responsible for Sox9-mediated transcription. We review here the discovery of this master chondrogenic trio and its roles in chondrogenesis in vivo and at the molecular level, and we discuss how these pioneering studies open the way for many additional studies that are needed to further increase our understanding of the transcriptional regulatory machinery operating in chondrogenesis.
自 1994 年发现 Sox9 突变与严重的人类骨骼畸形综合征——马方综合征有关以来, Sox9 被证明是软骨细胞特化和分化所必需和充分的。与此同时,它的远亲 Sox5 和 Sox6 被证明彼此冗余,以强有力地增强其功能。 Sox 三巨头目前最出名的是其激活软骨特异性细胞外基质成分基因的能力。 Sox9 和 Sox5/6 通过与其 Sry 相关的高迁移率组 DNA 结合域相邻的结构域同源二聚化,以增加其与软骨细胞特异性增强子协同结合的效率。 Sox9 具有强大的转录激活结构域,从而招募多种转录共激活因子、组蛋白修饰酶、中介复合物亚基和一般转录机制的组成部分,如 CBP/p300、Med12、Med25 和 Wwp2。这些信息帮助我们开始揭示 Sox9 介导的转录的机制。我们在这里回顾了这个主软骨形成三巨头的发现及其在体内和分子水平上的软骨发生中的作用,并讨论了这些开创性的研究如何为进一步增加我们对软骨发生中运行的转录调控机制的理解所需的许多其他研究开辟了道路。