title: Altered splicing leads to reduced activation of CPEB3 in high-grade gliomas.
abstract: Cytoplasmic polyadenylation element binding proteins (CPEBs) are auxiliary translational factors that associate with consensus sequences present in 3'UTRs of mRNAs, thereby activating or repressing their translation. Knowing that CPEBs are players in cell cycle regulation and cellular senescence prompted us to investigate their contribution to the molecular pathology of gliomas-most frequent of intracranial tumors found in humans. To this end, we performed methylation analyses in the promoter regions of CPEB1-4 and identified the CPEB1 gene to be hypermethylated in tumor samples. Decreased expression of CPEB1 protein in gliomas correlated with the rising grade of tumor malignancy. Abundant expression of CPEBs2-4 was observed in several glioma specimens. Interestingly, expression of CPEB3 positively correlated with tumor progression and malignancy but negatively correlated with protein phosphorylation in the alternatively spliced region. Our data suggest that loss of CPEB3 activity in high-grade gliomas is caused by expression of alternatively spliced variants lacking the B-region that overlaps with the kinase recognition site. We conclude that deregulation of CPEB proteins may be a frequent phenomenon in gliomas and occurs on the level of transcription involving epigenetic mechanism as well as on the level of mRNA splicing, which generates isoforms with compromised biological properties.
authors.affiliation: Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Skubal
authors.affiliation: Institute of Neuropathology, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
authors.forename: Gerrit H
authors.initials: GH
authors.lastname: Gielen
authors.affiliation: Institute of Neuropathology, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Waha
authors.affiliation: Institute of Neuropathology, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Gessi
authors.affiliation: Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, 53105 Bonn, Germany.|German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
authors.forename: Lech
authors.initials: L
authors.lastname: Kaczmarczyk
authors.affiliation: Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Seifert
authors.affiliation: Institute of Neuropathology, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Freihoff
authors.affiliation: Institute of Neuropathology, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Freihoff
authors.affiliation: Institute of Neuropathology, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.affiliation: Institute of Neurosurgery, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Simon
authors.affiliation: Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Theis
authors.affiliation: Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Steinhäuser
authors.affiliation: Institute of Neuropathology, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Waha
mesh_terms: D017398:Alternative Splicing; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D060787:Neoplasm Grading; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D059368:RNA Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C513866:CPEB3 protein, human; D020033:Protein Isoforms; D059368:RNA Isoforms; D012333:RNA, Messenger; D016601:RNA-Binding Proteins
keywords: CPEB; DNA methylation; expression; glioma; splicing