The effects of the unfolded protein response on medulloblastoma

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DESCRIPTION (provided by applicant): Medulloblastoma is a highly malignant pediatric brain tumor with a 5-year survival rate of ~ 60%. The sonic hedgehog (SHH) pathway plays a critical role in medulloblastoma development. Heterozygous deficiency of patched1 (PTCH1), a SHH receptor, in mice results in ~ 14% incidence of medulloblastoma. On the other hand, we have shown that transgenic mice that ectopically express immune cytokine interferon- ? (IFN-?) in the central nervous system during development display cerebellar dysplasia or medulloblastoma. Endoplasmic reticulum (ER) stress, initiated by the accumulation of unfolded or misfolded proteins, activates the unfolded protein response (UPR). The UPR activates pancreatic ER kinase (PERK), which coordinates an adaptive program by phosphorylating translation initiation factor 2a (eIF2a). Phosphorylation of eIF2a promotes a stress-resistant state through global attenuation of protein biosynthesis and induction of numerous stress- induced cytoprotective genes. Inactivation of growth arrest and DNA damage 34 (GADD34), a stress-inducible regulatory subunit of a phosphatase complex that dephosphorylates eIF2a, increases the level of phosphorylated eIF2a in stressed cells and adapts cells to various stresses. Adaptation to the tumor microenvironment is thought to be a key driver of malignancy after tumor cells accumulate mutations that overcome cell cycle and apoptotic checkpoints. Evidence is emerging that the UPR may play a role in this adaptation process. Interestingly, our preliminary observations suggest that the PERK pathway is activated in medulloblastoma in both IFN- ? -expressing transgenic mice and PTCH1 heterozygous deficient mice. Thus, our broad hypothesis is that the UPR promotes medulloblastoma development by adapting the tumor cells to various stresses in the tumor microenvironment such as hypoxia and nutrition deficiency, and renders the cells resistant to chemotherapy. The specific aims of this project are as follows: (1) to determine whether GADD34 inactivation enhances the activity of the PERK- eIF2a pathway and acts in synergy with IFN-? to induce medulloblastoma; (2) to determine whether activation of the PERK- eIF2a pathway promotes medulloblastoma development in PTCH1 heterozygous deficient mice; and (3) to determine whether the PERK pathway adapts human medulloblastoma cells to hypoxia and nutrition deficiency, and renders the cells resistant to chemotherapy agents. The significance of this proposed work is that it will shed light on the role of the UPR in medulloblastoma development and chemotherapy resistance. Such information is critical to developing novel therapeutic strategies for treating this disease.