Ohlmeyer J T, Kalderon D
Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Nature. 1998;396(6713):749-53. doi: 10.1038/25533.
In Drosophila, signalling by the protein Hedgehog (Hh) alters the activity of the transcription factor Cubitus interruptus (Ci) by inhibiting the proteolysis of full-length Ci (Ci-155) to its shortened Ci-75 form. Ci-75 is found largely in the nucleus and is thought to be a transcriptional repressor, whereas there is evidence to indicate that Ci-155 may be a transcriptional activator. However, Ci-155 is detected only in the cytoplasm, where it is associated with the protein kinase Fused (Fu), with Suppressor of Fused (Su(fu)), and with the microtubule-binding protein Costal-2. It is not clear how Ci-155 might become a nuclear activator. We show here that mutations in Su(fu) cause an increase in the expression of Hh-target genes in a dose-dependent manner while simultaneously reducing Ci-155 concentration by some mechanism other than proteolysis to Ci-75. Conversely, eliminating Fu kinase activity reduces Hh-target gene expression while increasing Ci-155 concentration. We propose that Fu kinase activity is required for Hh to stimulate the maturation of Ci-155 into a short-lived nuclear transcriptional activator and that Su(fu) opposes this maturation step through a stoichiometric interaction with Ci-155.
在果蝇中，刺猬蛋白（Hh）发出的信号通过抑制全长Ci（Ci-155）向缩短的Ci-75形式的蛋白水解作用，改变转录因子间断翅脉（Ci）的活性。Ci-75主要存在于细胞核中，被认为是一种转录抑制因子，而有证据表明Ci-155可能是一种转录激活因子。然而，Ci-155仅在细胞质中被检测到，它在细胞质中与蛋白激酶融合蛋白（Fu）、融合抑制因子（Su(fu)）以及微管结合蛋白肋骨-2相关联。目前尚不清楚Ci-155如何成为核激活因子。我们在此表明，Su(fu)中的突变以剂量依赖的方式导致Hh靶基因的表达增加，同时通过某种不同于蛋白水解为Ci-75的机制降低Ci-155的浓度。相反，消除Fu激酶活性会降低Hh靶基因的表达，同时增加Ci-155的浓度。我们提出，Fu激酶活性是Hh刺激Ci-155成熟为一种短命的核转录激活因子所必需的，并且Su(fu)通过与Ci-155的化学计量相互作用来对抗这一成熟步骤。
