Dual role of the integrated stress response in medulloblastoma tumorigenesis.
Dual role of the integrated stress response in medulloblastoma tumorigenesis.
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DOI：
10.18632/oncotarget.11873
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发表时间：
2016-09-27
期刊：
影响因子：
--
通讯作者：
Lin W
中科院分区：
文献类型：
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作者：
Stone S;Ho Y;Li X;Jamison S;Harding HP;Ron D;Lin W
在内质网（ER）应激反应中，胰腺内质网激酶（PERK）的激活通过磷酸化翻译起始因子2α (eIF2α)来协调一个被称为综合应激反应（ISR）的适应性程序。磷酸化的eIF2α被蛋白磷酸酶1和生长阻滞和DNA损伤34 （GADD34）复合体迅速去磷酸化。数据表明，ISR可以促进或抑制肿瘤的发展。我们之前的研究表明，在人类患者和动物模型中，ISR在成神经管细胞瘤中都被激活，并且通过PERK杂合缺陷降低ISR，通过增强细胞转化过程中恶性前颗粒细胞前体（GCPs）的凋亡，减轻了patche1杂合缺陷（Ptch1+/−）小鼠成神经管细胞瘤的形成。我们在这里发现，GADD34杂合突变适度增强了成年Ptch1+/−小鼠的ISR，并显著增加了成神经管细胞瘤的发生率。令人惊讶的是，GADD34纯合突变强烈增强了ISR，但显著降低了成年Ptch1+/−小鼠成神经管细胞瘤的发病率。有趣的是，GADD34纯合突变显著增强了小脑增生性病变中癌前GCP的凋亡，并减少了年轻Ptch1+/−小鼠的病变数量。然而，GADD34杂合突变和GADD34纯合突变对成年Ptch1+/−小鼠成神经管细胞瘤细胞均无显著影响。综上所述，这些数据表明ISR通过调节恶性转化过程中癌前gcp的凋亡，在成神经管细胞瘤的发生过程中具有促进和抑制的双重作用。
In response to endoplasmic reticulum (ER) stress, activation of pancreatic ER kinase (PERK) coordinates an adaptive program known as the integrated stress response (ISR) by phosphorylating translation initiation factor 2α (eIF2α). Phosphorylated eIF2α is quickly dephosphorylated by the protein phosphatase 1 and growth arrest and DNA damage 34 (GADD34) complex. Data indicate that the ISR can either promote or suppress tumor development. Our previous studies showed that the ISR is activated in medulloblastoma in both human patients and animal models, and that the decreased ISR via PERK heterozygous deficiency attenuates medulloblastoma formation in Patched1 heterozygous deficient (Ptch1+/−) mice by enhancing apoptosis of pre-malignant granule cell precursors (GCPs) during cell transformation. We showed here that GADD34 heterozygous mutation moderately enhanced the ISR and noticeably increased the incidence of medulloblastoma in adult Ptch1+/− mice. Surprisingly, GADD34 homozygous mutation strongly enhanced the ISR, but significantly decreased the incidence of medulloblastoma in adult Ptch1+/− mice. Intriguingly, GADD34 homozygous mutation significantly enhanced pre-malignant GCP apoptosis in cerebellar hyperplastic lesions and reduced the lesion numbers in young Ptch1+/− mice. Nevertheless, neither GADD34 heterozygous mutation nor GADD34 homozygous mutation had a significant effect on medulloblastoma cells in adult Ptch1+/− mice. Collectively, these data imply the dual role of the ISR, promoting and inhibiting, in medulloblastoma tumorigenesis by regulating apoptosis of pre-malignant GCPs during the course of malignant transformation.