Deleterious c-Cbl Exon Skipping Contributes to Human Glioma
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 s...
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doaj-704b0b31138a4dcba202dd3b2b8e55302020-11-24T23:17:02ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022015-06-0117651852410.1016/j.neo.2015.06.003Deleterious c-Cbl Exon Skipping Contributes to Human GliomaMin Woo Seong0Seung Hyeun Ka1Ji Ho Park2Jong Ho Park3Hee Min Yoo4Seung Wook Yang5Jung Mi Park6Dongeun Park7Soon Tae Lee8Jae Hong Seol9Chin Ha Chung10School of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, KoreaSchool of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, KoreaSchool of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, KoreaSchool of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, KoreaSchool of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, KoreaSchool of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, KoreaSchool of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, KoreaSchool of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, KoreaDepartment of Neurology, Seoul National University Hospital, Seoul, KoreaSchool of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, KoreaSchool of Biological Sciences and Institute for Protein Metabolism and Diseases, College of Natural Sciences, Seoul National University, Seoul, Koreac-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.http://www.sciencedirect.com/science/article/pii/S147655861500072X |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Min Woo Seong Seung Hyeun Ka Ji Ho Park Jong Ho Park Hee Min Yoo Seung Wook Yang Jung Mi Park Dongeun Park Soon Tae Lee Jae Hong Seol Chin Ha Chung |
spellingShingle |
Min Woo Seong Seung Hyeun Ka Ji Ho Park Jong Ho Park Hee Min Yoo Seung Wook Yang Jung Mi Park Dongeun Park Soon Tae Lee Jae Hong Seol Chin Ha Chung Deleterious c-Cbl Exon Skipping Contributes to Human Glioma Neoplasia: An International Journal for Oncology Research |
author_facet |
Min Woo Seong Seung Hyeun Ka Ji Ho Park Jong Ho Park Hee Min Yoo Seung Wook Yang Jung Mi Park Dongeun Park Soon Tae Lee Jae Hong Seol Chin Ha Chung |
author_sort |
Min Woo Seong |
title |
Deleterious c-Cbl Exon Skipping Contributes to Human Glioma |
title_short |
Deleterious c-Cbl Exon Skipping Contributes to Human Glioma |
title_full |
Deleterious c-Cbl Exon Skipping Contributes to Human Glioma |
title_fullStr |
Deleterious c-Cbl Exon Skipping Contributes to Human Glioma |
title_full_unstemmed |
Deleterious c-Cbl Exon Skipping Contributes to Human Glioma |
title_sort |
deleterious c-cbl exon skipping contributes to human glioma |
publisher |
Elsevier |
series |
Neoplasia: An International Journal for Oncology Research |
issn |
1476-5586 1522-8002 |
publishDate |
2015-06-01 |
description |
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. |
url |
http://www.sciencedirect.com/science/article/pii/S147655861500072X |
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