Differential regulation of Gli proteins by Sufu in the lung affects PDGF signaling and myofibroblast development.
Differential regulation of Gli proteins by Sufu in the lung affects PDGF signaling and myofibroblast development.
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DOI：
10.1016/j.ydbio.2014.05.014
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发表时间：
2014-08-15
影响因子：
2.7
通讯作者：
Chuang, Pao-Tien
中科院分区：
文献类型：
--
作者：
Lin, Chuwen;Chen, Miao-Hsueh;Yao, Erica;Song, Hai;Gacayan, Rhodora;Hui, Chi-chung;Chuang, Pao-Tien
哺乳动物 Hedgehog (Hh) 信号传导依赖于三个 Gli 转录因子来介导 Hh 反应。这一过程部分受到主要负调节因子 Sufu 的控制，通过其对 Gli 蛋白水平、分布和活性的影响。在本报告中，我们表明 Sufu 通过拮抗 Numb/Itch 来调节 Gli1 蛋白水平。否则，Numb/Itch 会诱导 Gli1 蛋白降解。这与 Sufu 对 Spop 介导的 Gli2/3 降解的抑制形成对比。因此，通过 Sufu 控制所有三个 Gli 基因的蛋白质水平是调节 Hh 反应的保守机制，尽管是通过不同的途径。这些基于细胞的检测结果在体内得到了进一步验证。在分析 Sufu 如何控制不同组织中的 Gli 蛋白时，我们发现肺部 Sufu 的缺失对 Hh 靶基因产生不同的影响。 Hh 靶标 Ptch1/Hhip 在 Sufu 缺陷的肺中上调，与 Hh 通路激活一致。令人惊讶的是，Hh 靶标 Gli1 的蛋白质水平降低了。我们还发现，缺乏腐乳的肺的许多预期肺泡中不存在肌成纤维细胞。肌成纤维细胞的发育依赖于 PDGF 信号传导。有趣的是，对 Pdgfra 启动子的分析揭示了 Gli1 所在的典型 Gli 结合位点。这些研究支持一个模型，其中 Sufu 的缺失会导致 Pdgfra 激活受损并破坏肺部肌成纤维细胞的发育。我们的工作说明了 Hh 反应未被认识到的复杂性，其中不同的 Hh 靶标可能会根据控制其表达的 Gli 蛋白的可用性而做出不同的反应。
Mammalian Hedgehog (Hh) signaling relies on three Gli transcription factors to mediate Hh responses. This process is controlled in part by a major negative regulator, Sufu, through its effects on Gli protein level, distribution and activity. In this report, we showed that Sufu regulates Gli1 protein levels by antagonizing Numb/Itch. Otherwise, Numb/Itch would induce Gli1 protein degradation. This is in contrast to inhibition of Spop-mediated degradation of Gli2/3 by Sufu. Thus, controlling protein levels of all three Gli genes by Sufu is a conserved mechanism to modulate Hh responses albeit via distinct pathways. These findings in cell-based assays were further validated in vivo. In analyzing how Sufu controls Gli proteins in different tissues, we discovered that loss of Sufu in the lung exerts different effects on Hh target genes. Hh targets Ptch1/Hhip are upregulated in Sufu-deficient lungs, consistent with Hh pathway activation. Surprisingly, protein levels of Hh target Gli1 are reduced. We also found that myofibroblasts are absent from many prospective alveoli of Sufu-deficient lungs. Myofibroblast development is dependent on PDGF signaling. Interestingly, analysis of the Pdgfra promoter revealed a canonical Gli-binding site where Gli1 resides. These studies support a model in which loss of Sufu contributes to compromised Pdgfra activation and disrupts myofibroblast development in the lung. Our work illustrates the unappreciated complexity of Hh responses where distinct Hh targets could respond differently depending on the availability of Gli proteins that control their expression.
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影响因子：
2.7
作者：
Cao, Ting;Wang, Chengbing;Wang, Baolin
通讯作者：
Wang, Baolin
影响因子：
5.3
作者：
Hamilton, TG;Klinghoffer, RA;Soriano, P
通讯作者：
Soriano, P
解码 Hedgehog 信号转导中的磷酸化密码
影响因子：
44.1
作者：
通讯作者：
--
影响因子：
2.9
作者：
Barnfield, PC;Zhang, XY;Hui, CC
通讯作者：
Hui, CC
DOI：
10.1152/ajpgi.00564.2007
发表时间：
2008-04-01
影响因子：
4.5
作者：
Farzan, Shohreh F.;Singh, Samer;Robbins, David J.
通讯作者：
Robbins, David J.