Oncotarget

Research Papers:

Altered splicing leads to reduced activation of CPEB3 in high-grade gliomas

Magdalena Skubal, Gerrit H. Gielen, Anke Waha, Marco Gessi, Lech Kaczmarczyk, Gerald Seifert, Dorothee Freihoff, Johannes Freihoff, Torsten Pietsch, Matthias Simon, Martin Theis, Christian Steinhäuser and Andreas Waha _

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Oncotarget. 2016; 7:41898-41912. https://doi.org/10.18632/oncotarget.9735

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Abstract

Magdalena Skubal1, Gerrit H. Gielen2, Anke Waha2, Marco Gessi2, Lech Kaczmarczyk1,3, Gerald Seifert1, Dorothee Freihoff2, Johannes Freihoff2, Torsten Pietsch2, Matthias Simon4, Martin Theis1, Christian Steinhäuser1, Andreas Waha2

1Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, 53105 Bonn, Germany

2Institute of Neuropathology, Medical Faculty, University of Bonn, 53105 Bonn, Germany

3German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany

4Institute of Neurosurgery, Medical Faculty, University of Bonn, 53105 Bonn, Germany

Correspondence to:

Andreas Waha, email: awaha@uni-bonn.de

Keywords: CPEB, glioma, DNA methylation, splicing, expression

Received: December 17, 2015     Accepted: May 13, 2016     Published: May 31, 2016

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.


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