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.
Highlights
Control of mRNA polyadenylation is an important step in regulation of gene expression
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 have identified CPEB1 as a target for epigenetic inactivation by differential methylation hybridization (DMH)
Summary
Control of mRNA polyadenylation is an important step in regulation of gene expression. Cytoplasmic polyadenylation element binding (CPEB) proteins activate or inhibit translation of mRNA molecules by binding to the consensus CPE sequences present in the 3′untranslated regions of transcripts [1, 2]. In basal conditions, when the activity of PARN deadenylase exceeds Gld polymerase, CPEBs promote translational repression by holding the bound mRNAs in a dormant state. Recent findings indicate that CPEB1 contributes to various biological processes like synaptic plasticity [10], mitotic cell cycle control [11, 12] and cellular senescence of murine [13] or human fibroblasts [14]. Inhibition of CPEB1 activity results in the Warburg effect characterized by metabolic changes in cells, like elevated glycolysis, reduced cellular respiration and generation of reactive oxygen species at constant ATP content [14]
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