title: PERK Activation Promotes Medulloblastoma Tumorigenesis by Attenuating Premalignant Granule Cell Precursor Apoptosis.
abstract: Evidence suggests that activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum stress negatively or positively influences cell transformation by regulating apoptosis. Patched1 heterozygous deficient (Ptch1(+/-)) mice reproduce human Gorlin's syndrome and are regarded as the best animal model to study tumorigenesis of the sonic hedgehog subgroup of medulloblastomas. It is believed that medulloblastomas in Ptch1(+/-) mice results from the transformation of granule cell precursors (GCPs) in the developing cerebellum. Here, we determined the role of PERK signaling on medulloblastoma tumorigenesis by assessing its effects on premalignant GCPs and tumor cells. We found that PERK signaling was activated in both premalignant GCPs in young Ptch1(+/-) mice and medulloblastoma cells in adult mice. We demonstrated that PERK haploinsufficiency reduced the incidence of medulloblastomas in Ptch1(+/-) mice. Interestingly, PERK haploinsufficiency enhanced apoptosis of premalignant GCPs in young Ptch1(+/-) mice but had no significant effect on medulloblastoma cells in adult mice. Moreover, we showed that the PERK pathway was activated in medulloblastomas in humans. These results suggest that PERK signaling promotes medulloblastoma tumorigenesis by attenuating apoptosis of premalignant GCPs during the course of malignant transformation.
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Yeung
authors.initials: Y
authors.lastname: Ho
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Periodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiting
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jamison
authors.affiliation: Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Heather P
authors.initials: HP
authors.lastname: Harding
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
authors.affiliation: Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Electronic address: linw@umn.edu.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Lin
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D002528:Cerebellar Neoplasms / Q000201:enzymology / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D058953:Neural Stem Cells / Q000473:pathology*; D009474:Neurons / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D019892:eIF-2 Kinase