A deregulated integrated stress response promotes interferon-γ-induced medulloblastoma.

Abstract

Endoplasmic reticulum (ER) stress activates pancreatic ER kinase (PERK), which coordinates an adaptive program known as the integrated stress response (ISR) by phosphorylating translation initiation factor 2α (eIF2α). There is evidence that the ISR is involved in tumor development. Recent studies also show that the ISR stimulates the expression of vascular endothelial growth factor A (VEGF-A), a master regulator of angiogenesis. Our previous studies have demonstrated that enforced expression of interferon-γ (IFNγ) in the central nervous system during development induces sonic hedgehog expression and leads to cerebellar dysplasia or medulloblastoma. Here we report that PERK was activated in cerebellar dysplasia and medulloblastoma in IFNγ-expressing mice. We found that inactivation of the growth arrest and DNA damage 34 (GADD34) gene, encoding the stress-inducible regulatory subunit of a phosphatase complex that dephosphorylates eIF2α, enhanced ISR signaling and facilitated medulloblastoma formation in IFNγ-expressing mice. Moreover, we found that the induction of VEGF-A and enhanced angiogenesis were associated with medulloblastoma formation in IFNγ-expressing mice on the GADD34 mutation background. Thus, our data provide genetic evidence that the ISR facilitates medulloblastoma development.