Abstract
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.
Highlights
Activation of pancreatic endoplasmic reticulum kinase (PERK), in response to endoplasmic reticulum (ER) stress, coordinates an adaptive program known as the integrated stress response (ISR, Figure 1) by phosphorylating the α subunit of the eukaryotic translation initiation factor 2 [1, 2, 3]
Evidence is emerging that the pancreatic ER kinase (PERK)-mediated ISR can either promote or suppress tumorigenesis by regulating cell apoptosis during the course of malignant transformation [12, 13, 14, 17]
Using PERK heterozygous deficient mice, our previous study showed that the decreased ISR reduces the incidence of medulloblastoma in Ptch1+/− mice by enhancing pre-malignant granule cell precursors (GCPs) apoptosis during cell transformation [27]
Summary
Activation of pancreatic endoplasmic reticulum kinase (PERK), in response to endoplasmic reticulum (ER) stress, coordinates an adaptive program known as the integrated stress response (ISR, Figure 1) by phosphorylating the α subunit of the eukaryotic translation initiation factor 2 (eIF2α) [1, 2, 3]. Phosphorylation of eIF2α inhibits global protein translation but stimulates the expression of certain stress-induced genes through induction of the transcription factor ATF4. Induction of ATF4 by p-eIF2α stimulates the expression of the transcription factor CAATT enhancer binding protein homologous protein (CHOP), and results in upregulation of GADD34, which forms a tight autofeedback loop regulating activity of the ISR [6, 7, 8]. Some reports showed that the ISR attenuates cell apoptosis during malignant transformation and/or after malignant transformation, resulting in enhanced tumor development [10, 12]. Other reports showed that the ISR elevates cell apoptosis during malignant transformation and/or after malignant transformation, resulting in attenuated tumor development [13, 18]
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