Deactivation of the beta-catenin transactivating complex

The mechanisms involved in downregulation of TCF-dependent transcription are not yet very well understood. beta-catenin is known to recruit a number of transcriptional repressors, including Reptin, SMRT and NCoR, to the TCF/LEF complex, allowing the transition from activation to repression (Bauer et al, 2000; Weiske et al, 2007; Song and Gelmann, 2008). CTNNBIP1 (also known as ICAT) and Chibby are inhibitors of TCF-dependent signaling that function by binding directly to beta-catenin and preventing interactions with critical components of the transactivation machinery (Takemaru et al, 2003; Li et al, 2008; Tago et al, 2000; Graham et al, 2002; Daniels and Weiss, 2002). Chibby additionally promotes the nuclear export of beta-catenin in conjunction with 14-3-3/YWHAZ proteins (Takemura et al, 2003; Li et al, 2008). A couple of recent studies have also suggested a role for nuclear APC in the disassembly of the beta-catenin activation complex (Hamada and Bienz, 2004; Sierra et al, 2006). It is worth noting that while some of the players involved in the disassembly of the beta-catenin transactivating complex are beginning to be worked out in vitro, the significance of their role in vivo is not yet fully understood, and some can be knocked out with little effect on endogenous WNT signaling (see for instance Voronina et al, 2009).

涉及TCF依赖性转录下调的机制尚未得到充分的理解。已知β-连环蛋白能够募集一系列转录抑制因子，包括Reptin、SMRT和NCoR，至TCF/LEF复合体，从而实现从激活到抑制的转变（Bauer等，2000；Weiske等，2007；Song和Gelmann，2008）。CTNNBIP1（亦称ICAT）和Chibby是TCF依赖性信号通路的抑制剂，它们通过直接结合β-连环蛋白，阻止其与转激活机器的关键组成部分的相互作用（Takemaru等，2003；Li等，2008；Tago等，2000；Graham等，2002；Daniels和Weiss，2002）。此外，Chibby还与14-3-3/YWHAZ蛋白协同促进β-连环蛋白的核输出（Takemura等，2003；Li等，2008）。近期的一些研究亦表明，核APC在β-连环蛋白激活复合体的解聚过程中发挥着作用（Hamada和Bienz，2004；Sierra等，2006）。值得注意的是，尽管在体外已经开始解析参与β-连环蛋白转激活复合体解聚的一些角色，但它们在体内的意义尚不完全明了，并且其中一些角色即使被敲除，对内源性WNT信号通路的影响也微乎其微（例如，参见Voronina等，2009年）。