Negative regulation of Gli1 and Gli2 activator function by suppressor of fused through multiple mechanisms
Negative regulation of Gli1 and Gli2 activator function by suppressor of fused through multiple mechanisms
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DOI：
10.1111/j.1432-0436.2005.00042.x
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发表时间：
2005-10-01
期刊：
影响因子：
2.9
通讯作者：
Hui, CC
中科院分区：
文献类型：
--
作者：
Barnfield, PC;Zhang, XY;Hui, CC
在动物发育过程中，Hedgehog（Hh）信号转导通路在细胞命运决定和组织模式形成中起着关键作用。在人类中，异常的Hh信号传导与几种遗传疾病和癌症有关。Hh与其受体的结合启动信号级联，其最终导致Gli/Ci转录因子的激活。Suppressor of fused（Su（fu））是一种Gli/Ci相互作用蛋白，在果蝇和脊椎动物中作为Hh信号的负调控因子。Su（fu）也被认为是一种肿瘤抑制因子，因为它的突变在成神经管细胞瘤和前列腺癌中被发现。Su（fu）被认为是通过阻止Gli/Ci的核积累而起作用的，然而，对其作用模式的机械见解仍然难以捉摸。我们在这里证明，苏（fu）通过多种机制防止Gli 1和Gli 2的核积累。虽然Su（fu）本身不受CRM 1依赖性调节，但Su（fu）主要通过依赖于核输出蛋白CRM 1活性的机制在细胞质中隔离Gli 1。相反，Su（fu）螯合Gli 2不需要CRM 1介导的输出。此外，我们表明，在没有细胞质螯合的情况下，Su（fu）的N-末端足以使Gli失活。总之，这些观察结果表明，苏（fu）通过不同的细胞质和核机制调节Gli 1和Gli 2的活性。
During animal development, the Hedgehog (Hh) signal transduction pathway plays critical roles in cell fate determination and tissue patterning. In humans, aberrant Hh signaling has been linked to several genetic disorders and cancers. Binding of Hh to its receptor initiates a signaling cascade, which ultimately results in the activation of the Gli/Ci transcription factors. Suppressor of fused (Su(fu)) is a Gli/Ci-interacting protein, which acts as a negative regulator of Hh signaling in Drosophila and vertebrates. Su(fu) is also implicated as a tumor suppressor as its mutations have been found in medulloblastoma and prostate cancer. Su(fu) is thought to act by preventing the nuclear accumulation of Gli/Ci, however, mechanistic insight into its mode of action has remained elusive. We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms. While Su(fu) itself is not subject to CRM1-dependent regulation, Su(fu) sequesters Gli1 in the cytoplasm mostly through a mechanism that depends on the activity of the nuclear export protein CRM1. In contrast, CRM1-mediated export is not required for Su(fu) to sequester Gli2. Furthermore, we show that the N-terminus of Su(fu) is sufficient for Gli inactivation in the absence of cytoplasmic sequestration. Together, these observations reveal that Su(fu) regulates the activity of Gli1 and Gli2 through distinct cytoplasmic and nuclear mechanisms.