Zhang Qing, Zhang Lei, Wang Bing, Ou Chan-Yen, Chien Cheng-Ting, Jiang Jin
Center for Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
Dev Cell. 2006 Jun;10(6):719-29. doi: 10.1016/j.devcel.2006.05.004.
The Ci/Gli family of transcription factors mediates Hedgehog (Hh) signaling in many key developmental processes. Here we identify a Hh-induced MATH and BTB domain containing protein (HIB) as a negative regulator of the Hh pathway. Overexpressing HIB down regulates Ci and blocks Hh signaling, whereas inactivating HIB results in Ci accumulation and enhanced pathway activity. HIB binds the N- and C-terminal regions of Ci, both of which mediate Ci degradation. HIB forms a complex with Cul3, a scaffold for modular ubiquitin ligases, and promotes Ci ubiquitination and degradation through Cul3. Furthermore, HIB-mediated Ci degradation is stimulated by Hh and inhibited by Suppressor of Fused (Sufu). The mammalian homolog of HIB, SPOP, can functionally substitute for HIB, and Gli proteins are degraded by HIB/SPOP in Drosophila. We provide evidence that HIB prevents aberrant Hh signaling posterior to the morphogenic furrow, which is essential for normal eye development.
Ci/Gli转录因子家族在许多关键发育过程中介导刺猬信号通路（Hh信号通路）。在此，我们鉴定出一种含有MATH和BTB结构域的Hh诱导蛋白（HIB），它是Hh信号通路的负调控因子。过表达HIB会下调Ci并阻断Hh信号，而使HIB失活则导致Ci积累并增强信号通路活性。HIB与Ci的N端和C端区域结合，这两个区域均介导Ci的降解。HIB与Cul3（一种模块化泛素连接酶的支架蛋白）形成复合物，并通过Cul3促进Ci的泛素化和降解。此外，HIB介导的Ci降解受Hh刺激，并被融合抑制因子（Sufu）抑制。HIB的哺乳动物同源物SPOP在功能上可替代HIB，并且Gli蛋白在果蝇中会被HIB/SPOP降解。我们提供的证据表明，HIB可防止形态发生沟后方出现异常的Hh信号，这对正常眼睛发育至关重要。
