title: Deleterious c-Cbl Exon Skipping Contributes to Human Glioma.
abstract: c-Cbl, a RING-type ubiquitin E3 ligase, downregulates various receptor tyrosine kinases (e.g., epidermal growth factor receptor (EGFR)), leading to inhibition of cell proliferation. Moreover, patients with myeloid neoplasm frequently harbor c-Cbl mutations, implicating the role of c-Cbl as a tumor suppressor. Recently, we have shown that c-Cbl downregulates αPix-mediated cell migration and invasion, and the lack of c-Cbl in the rat C6 and human A172 glioma cells is responsible for their malignant behavior. Here, we showed that c-Cbl exon skipping occurs in the glioma cells and the brain tissues from glioblastoma patients lacking c-Cbl. This exon skipping resulted in generation of two types of c-Cbl isoforms: type I lacking exon-9 and type II lacking exon-9 and exon-10. However, the c-Cbl isoforms in the cells and tissues could not be detected as they were rapidly degraded by proteasome. Consequently, C6 and A172 cells showed sustained EGFR activation. However, no splice site mutation was found in the region from exon-7 to exon-11 of the c-Cbl gene in C6 cells and a glioblastoma tissue lacking c-Cbl. In addition, c-Cbl exon skipping could be induced when cells transfected with a c-Cbl mini-gene were grown to high density or under hypoxic stress. These results suggest that unknown alternations (e.g., mutation) of splicing machinery in C6 and A172 cells and the glioblastoma brain tissues are responsible for the deleterious exon skipping. Collectively, these findings indicate that the c-Cbl exon skipping contributes to human glioma and its malignant behavior.
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, Korea.
authors.forename: Min Woo
authors.initials: MW
authors.lastname: Seong
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, Korea.
authors.forename: Seung Hyeun
authors.initials: SH
authors.lastname: Ka
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, Korea.
authors.forename: Ji Ho
authors.initials: JH
authors.lastname: Park
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, Korea.
authors.forename: Jong Ho
authors.initials: JH
authors.lastname: Park
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, Korea.
authors.forename: Hee Min
authors.initials: HM
authors.lastname: Yoo
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, Korea.
authors.forename: Seung Wook
authors.initials: SW
authors.lastname: Yang
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, Korea.
authors.forename: Jung Mi
authors.initials: JM
authors.lastname: Park
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, Korea.
authors.forename: Dongeun
authors.initials: D
authors.lastname: Park
authors.affiliation: Department of Neurology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Soon Tae
authors.initials: ST
authors.lastname: Lee
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, Korea. Electronic address: jhseol@snu.ac.kr.
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seol
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, Korea. Electronic address: chchung@snu.ac.kr.
authors.forename: Chin Ha
authors.initials: CH
authors.lastname: Chung
mesh_terms: D000818:Animals; D015153:Blotting, Western; D066246:ErbB Receptors / Q000235:genetics; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D047468:Immunoprecipitation; D009154:Mutation / Q000235:genetics; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D050436:Regulatory Elements, Transcriptional; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D050721:Proto-Oncogene Proteins c-cbl; C512478:EGFR protein, human; D066246:ErbB Receptors; C067419:CBL protein, human