Hoogeboom Diana, Essers Marieke A G, Polderman Paulien E, Voets Erik, Smits Lydia M M, Burgering Boudewijn M Th
Department of Physiological Chemistry, Center for Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
J Biol Chem. 2008 Apr 4;283(14):9224-30. doi: 10.1074/jbc.M706638200. Epub 2008 Feb 4.
Wingless (Wnt) signaling regulates many aspects of development and tissue homeostasis, and aberrant Wnt signaling can lead to cancer. Upon a Wnt signal beta-catenin degradation is halted and consequently the level of beta-catenin in the cytoplasm increases. This allows entry of beta-catenin into the nucleus where it can regulate gene transcription by direct binding to members of the lymphoid enhancer factor/T cell factor (TCF) family of transcription factors. Recently, we identified Forkhead box-O (FOXO) transcription factors as novel interaction partners of beta-catenin (Essers, M. A., de Vries-Smits, L. M., Barker, N., Polderman, P. E., Burgering, B. M., and Korswagen, H. C. (2005) Science 308, 1181-1184). Here we show that the beta-catenin binding to FOXO serves a dual effect. beta-catenin, through binding, enhances FOXO transcriptional activity. In addition, FOXO competes with TCF for interaction with beta-catenin, thereby inhibiting TCF transcriptional activity. Reduced binding between TCF and beta-catenin is observed after FOXO overexpression and cellular oxidative stress, which simultaneously increases binding between beta-catenin and FOXO. Furthermore, small interfering RNA-mediated knock down of FOXO reverts loss of beta-catenin binding to TCF after cellular oxidative stress. Taken together, these results provide evidence for a cross-talk mechanism between FOXO and TCF signaling in which beta-catenin plays a central regulatory role.
无翅型（Wnt）信号通路调控发育和组织稳态的多个方面，Wnt信号通路异常可导致癌症。在Wnt信号作用下，β-连环蛋白的降解停止，因此细胞质中β-连环蛋白的水平升高。这使得β-连环蛋白进入细胞核，在细胞核中它可以通过直接结合淋巴样增强因子/T细胞因子（TCF）转录因子家族的成员来调节基因转录。最近，我们鉴定出叉头框O（FOXO）转录因子是β-连环蛋白的新型相互作用伙伴（埃瑟斯，M.A.，德弗里斯-斯米茨，L.M.，巴克，N.，波尔德曼，P.E.，布尔热林，B.M.，和科斯瓦根，H.C.（2005年）《科学》308卷，1181 - 1184页）。在此我们表明，β-连环蛋白与FOXO的结合具有双重作用。β-连环蛋白通过结合增强FOXO的转录活性。此外，FOXO与TCF竞争与β-连环蛋白的相互作用，从而抑制TCF的转录活性。在FOXO过表达和细胞氧化应激后，观察到TCF与β-连环蛋白之间的结合减少，同时β-连环蛋白与FOXO之间的结合增加。此外，小干扰RNA介导的FOXO敲低可逆转细胞氧化应激后β-连环蛋白与TCF结合的丧失。综上所述，这些结果为FOXO和TCF信号通路之间的相互作用机制提供了证据，其中β-连环蛋白起着核心调节作用。
