Roadkill attenuates Hedgehog responses through degradation of Cubitus interruptus
Roadkill attenuates Hedgehog responses through degradation of Cubitus interruptus
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DOI：
10.1242/dev.02370
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发表时间：
2006-05-15
期刊：
影响因子：
4.6
通讯作者：
Hooper, JE
中科院分区：
文献类型：
--
作者：
Kent, D;Bush, EW;Hooper, JE
Hedgehog（Hh）信号转导的最后一步是转录因子Cubitus interruptus（Ci）的翻译后调节。Ci以潜伏形式存在于细胞质中，其中Hh调节其加工成转录阻遏物或其作为转录激活剂进入核。潜伏Ci的水平由降解控制，不同的途径响应于不同水平的Hh而被激活。在这里，我们描述了roadkill（rdx）基因，这是在响应Hh的表达。Rdx蛋白属于保守的蛋白质家族，其充当Cullin 3介导的泛素化的底物衔接子。rdx的过表达降低了Ci水平，降低了Ci介导的转录激活和抑制。rdx的损失允许Ci的过度积累。在眼睛中的rdx操作揭示了Hh在色素和视锥细胞的组织和存活中的新作用。这些研究将rdx确定为反馈回路中的限制因素，该反馈回路通过降低Ci水平来衰减Hh反应。Rdx的人类直系同源物的存在提出了这种新的反馈回路也调节人类Hh反应的可能性。
The final step in Hedgehog (Hh) signal transduction is post-translational regulation of the transcription factor, Cubitus interruptus (Ci). Ci resides in the cytoplasm in a latent form, where Hh regulates its processing into a transcriptional repressor or its nuclear access as a transcriptional activator. Levels of latent Ci are controlled by degradation, with different pathways activated in response to different levels of Hh. Here, we describe the roadkill (rdx) gene, which is expressed in response to Hh. The Rdx protein belongs to a conserved family of proteins that serve as substrate adaptors for Cullin3-mediated ubiquitylation. Overexpression of rdx reduced Ci levels and decreased both transcriptional activation and repression mediated by Ci. Loss of rdx allowed excessive accumulation of Ci. rdx manipulation in the eye revealed a novel role for Hh in the organization and survival of pigment and cone cells. These studies identify rdx as a limiting factor in a feedback loop that attenuates Hh responses through reducing levels of Ci. The existence of human orthologs for Rdx raises the possibility that this novel feedback loop also modulates Hh responses in humans.