当前位置: X-MOL 学术PLOS ONE › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1.
PLOS ONE ( IF 2.9 ) Pub Date : 2013-06-10 , DOI: 10.1371/journal.pone.0065403
Frank Götschel 1 , Daniela Berg , Wolfgang Gruber , Christian Bender , Markus Eberl , Myriam Friedel , Johanna Sonntag , Elena Rüngeler , Hendrik Hache , Christoph Wierling , Wilfried Nietfeld , Hans Lehrach , Annemarie Frischauf , Reinhard Schwartz-Albiez , Fritz Aberger , Ulrike Korf
Affiliation  

Aberrant activation of Hedgehog (HH) signaling has been identified as a key etiologic factor in many human malignancies. Signal strength, target gene specificity, and oncogenic activity of HH signaling depend profoundly on interactions with other pathways, such as epidermal growth factor receptor-mediated signaling, which has been shown to cooperate with HH/GLI in basal cell carcinoma and pancreatic cancer. Our experimental data demonstrated that the Daoy human medulloblastoma cell line possesses a fully inducible endogenous HH pathway. Treatment of Daoy cells with Sonic HH or Smoothened agonist induced expression of GLI1 protein and simultaneously prevented the processing of GLI3 to its repressor form. To study interactions between HH- and EGF-induced signaling in greater detail, time-resolved measurements were carried out and analyzed at the transcriptomic and proteomic levels. The Daoy cells responded to the HH/EGF co-treatment by downregulating GLI1, PTCH, and HHIP at the transcript level; this was also observed when Amphiregulin (AREG) was used instead of EGF. We identified a novel crosstalk mechanism whereby EGFR signaling silences proteins acting as negative regulators of HH signaling, as AKT- and ERK-signaling independent process. EGFR/HH signaling maintained high GLI1 protein levels which contrasted the GLI1 downregulation on the transcript level. Conversely, a high-level synergism was also observed, due to a strong and significant upregulation of numerous canonical EGF-targets with putative tumor-promoting properties such as MMP7, VEGFA, and IL-8. In conclusion, synergistic effects between EGFR and HH signaling can selectively induce a switch from a canonical HH/GLI profile to a modulated specific target gene profile. This suggests that there are more wide-spread, yet context-dependent interactions, between HH/GLI and growth factor receptor signaling in human malignancies.

中文翻译:

Hedgehog 反应性人髓母细胞瘤细胞中 Hedgehog-GLI 和 EGFR 信号传导之间的协同作用诱导典型 Hedgehog 靶基因的下调和 GLI1 的稳定表达。

Hedgehog (HH) 信号的异常激活已被确定为许多人类恶性肿瘤的关键病因。HH 信号的信号强度、靶基因特异性和致癌活性在很大程度上取决于与其他途径的相互作用,例如表皮生长因子受体介导的信号,已被证明在基底细胞癌和胰腺癌中与 HH/GLI 合作。我们的实验数据表明 Daoy 人髓母细胞瘤细胞系具有完全可诱导的内源性 HH 通路。用 Sonic HH 或 Smoothened 激动剂处理 Daoy 细胞可诱导 GLI1 蛋白的表达,同时阻止 GLI3 加工为其阻遏物形式。为了更详细地研究 HH 和 EGF 诱导的信号传导之间的相互作用,在转录组学和蛋白质组学水平上进行和分析了时间分辨测量。Daoy 细胞通过在转录水平下调 GLI1、PTCH 和 HHIP 来响应 HH/EGF 共处理;当使用双调节蛋白 (AREG) 代替 EGF 时也观察到了这一点。我们确定了一种新的串扰机制,即 EGFR 信号使作为 HH 信号负调节器的蛋白质沉默,作为 AKT 和 ERK 信号独立过程。EGFR/HH 信号维持高 GLI1 蛋白水平,这与转录水平上的 GLI1 下调形成对比。相反,由于具有推定的肿瘤促进特性(如 MMP7、VEGFA 和 IL-8)的众多经典 EGF 靶标的强烈和显着上调,也观察到了高水平的协同作用。综上所述,EGFR 和 HH 信号传导之间的协同效应可以选择性地诱导从典型的 HH/GLI 谱向调节的特定靶基因谱的转变。这表明在人类恶性肿瘤中 HH/GLI 和生长因子受体信号传导之间存在更广泛但依赖于上下文的相互作用。
更新日期:2019-11-01
down
wechat
bug