New GFAP splice isoform (GFAPµ) differentially expressed in glioma translates into 21 kDa N-terminal GFAP protein
van Bodegraven, Emma J.; Sluijs, Jacqueline A.; Tan, A. Katherine; Robe, Pierre A.J.T.; Hol, Elly M.
(2021) FASEB Journal, volume 35, issue 3, pp. 1 - 14
(Article)
Abstract
The glial fibrillary acidic protein (GFAP) is a type III intermediate filament (IF) protein that is highly expressed in astrocytes, neural stem cells, and in gliomas. Gliomas are a heterogeneous group of primary brain tumors that arise from glia cells or neural stem cells and rely on accurate diagnosis for
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prognosis and treatment strategies. GFAP is differentially expressed between glioma subtypes and, therefore, often used as a diagnostic marker. However, GFAP is highly regulated by the process of alternative splicing; many different isoforms have been identified. Differential expression of GFAP isoforms between glioma subtypes suggests that GFAP isoform-specific analyses could benefit diagnostics. In this study we report on the differential expression of a new GFAP isoform between glioma subtypes, GFAPµ. A short GFAP transcript resulting from GFAP exon 2 skipping was detected by RNA sequencing of human glioma. We show that GFAPµ mRNA is expressed in healthy brain tissue, glioma cell lines, and primary glioma cells and that it translates into a ~21 kDa GFAP protein. 21 kDa GFAP protein was detected in the IF protein fraction isolated from human spinal cord as well. We further show that induced GFAPµ expression disrupts the GFAP IF network. The characterization of this new GFAP isoform adds on to the numerous previously identified GFAP splice isoforms. It emphasizes the importance of studying the contribution of IF splice variants to specialized functions of the IF network and to glioma research.
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Keywords: alternative splicing, GFAP, GFAP isoforms, glioma, intermediate filaments, Glioma/metabolism, Protein Biosynthesis, Alternative Splicing, Humans, Glial Fibrillary Acidic Protein/biosynthesis, Brain Neoplasms/metabolism, Vimentin/chemistry, Protein Isoforms, Cell Line, Tumor, Brain/metabolism, Genetics, Molecular Biology, Biochemistry, Biotechnology, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 0892-6638
Publisher: FASEB
Note: Funding Information: The authors thank Vanessa Marques Donega and Marjolein Sneeboer for providing us with RNA samples of primary adult neural stem cells and human brain tissue. The results shown here are in part based on data generated by the TCGA Research Network: http://cancergenome.nih.gov/. This work was supported by the Netherlands Organization for Scientific Research (NWO; VICI grant 865.09.003), the T&P Bohnenn fund, the Dutch Cancer Society (KWF 10123), and the Netherlands Brain Bank (NBB), which is supported by the Netherlands Organization for Scientific Research (NWO). Publisher Copyright: © 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
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