Méthot N, Basler K
Institut für Molekularbiologie, Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Development. 2000 Sep;127(18):4001-10. doi: 10.1242/dev.127.18.4001.
Hedgehog controls the expression of key developmental genes through the conversion of the transcription factor Cubitus interruptus (Ci) into either an activator (Ci[act]) or a repressor (Ci[rep]) form. Proteolytic cleavage of full-length Ci is important for the generation of Ci[rep], but little is known about how Ci[act] arises in response to Hh. Here we examine Hh signal transduction components for their role in the conversion of full-length Ci into either Ci[act] or Ci[rep]. We report that Cos2, PKA and Fused are necessary for the generation of Ci[rep], whereas the inhibition of either Cos2 or PKA activity is a prerequisite for Ci[act] formation. Fused (Fu) kinase stimulates a constitutively active form of Ci in a Hh-dependent manner, suggesting that Fu enhances the activity rather than the formation of Ci[act]. Su(fu) reduces the nuclear accumulation of the constitutively active form of Ci, arguing that Su(fu) can function subsequent to Ci[act] formation. We propose that Hh induces target gene expression by a two-step mechanism in which Ci[act] is first formed and then accumulates in the nucleus via Fu-induced neutralization of Su(fu) activity.
刺猬因子通过将转录因子间断翅脉（Ci）转化为激活形式（Ci[act]）或抑制形式（Ci[rep]）来控制关键发育基因的表达。全长Ci的蛋白水解切割对于Ci[rep]的产生很重要，但对于Ci[act]如何响应刺猬因子（Hh）产生却知之甚少。在这里，我们研究了Hh信号转导成分在将全长Ci转化为Ci[act]或Ci[rep]过程中的作用。我们报告，Cos2、蛋白激酶A（PKA）和融合蛋白（Fused）对于Ci[rep]的产生是必需的，而抑制Cos2或PKA活性是Ci[act]形成的先决条件。融合蛋白激酶（Fu）以依赖Hh的方式刺激Ci的组成型活性形式，这表明Fu增强了Ci[act]的活性而非其形成。Suppressor of Fused（Su(fu)）减少了Ci组成型活性形式的核积累，这表明Su(fu)可以在Ci[act]形成之后发挥作用。我们提出，Hh通过两步机制诱导靶基因表达，其中首先形成Ci[act]，然后通过Fu诱导的Su(fu)活性中和作用使其在细胞核中积累。
