Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Genes Dev. 2010 Apr 1;24(7):670-82. doi: 10.1101/gad.1902910.
The transcriptional program orchestrated by Hedgehog signaling depends on the Gli family of transcription factors. Gli proteins can be converted to either transcriptional activators or truncated transcriptional repressors. We show that the interaction between Gli3 and Suppressor of Fused (Sufu) regulates the formation of either repressor or activator forms of Gli3. In the absence of signaling, Sufu restrains Gli3 in the cytoplasm, promoting its processing into a repressor. Initiation of signaling triggers the dissociation of Sufu from Gli3. This event prevents formation of the repressor and instead allows Gli3 to enter the nucleus, where it is converted into a labile, differentially phosphorylated transcriptional activator. This key dissociation event depends on Kif3a, a kinesin motor required for the function of primary cilia. We propose that the Sufu-Gli3 interaction is a major control point in the Hedgehog pathway, a pathway that plays important roles in both development and cancer.
Hedgehog 信号通路所调控的转录程序依赖于 Gli 家族转录因子。Gli 蛋白可以转化为转录激活剂或截短的转录抑制剂。我们发现 Gli3 和 Suppressor of Fused（Sufu）之间的相互作用调节了 Gli3 形成抑制物或激活物的形式。在没有信号的情况下，Sufu 将 Gli3 限制在细胞质中，促进其转化为抑制物。信号的起始触发 Sufu 与 Gli3 的解离。这一事件阻止了抑制物的形成，而是允许 Gli3 进入细胞核，在那里它被转化为不稳定的、差异磷酸化的转录激活剂。这个关键的解离事件依赖于 Kif3a，这是一种驱动蛋白，是初级纤毛功能所必需的。我们提出，Sufu-Gli3 相互作用是 Hedgehog 通路中的一个主要控制点，该通路在发育和癌症中都起着重要作用。
