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Differential roles of Epac in regulating cell death in neuronal and myocardial cells.

ABSTRACT: Cell survival and death play critical roles in tissues composed of post-mitotic cells. Cyclic AMP (cAMP) has been known to exert a distinct effect on cell susceptibility to apoptosis, protecting neuronal cells and deteriorating myocardial cells. These effects are primarily studied using protein kinase A activation. In this study we show the differential roles of Epac, an exchange protein activated by cAMP and a new effector molecule of cAMP signaling, in regulating apoptosis in these cell types. Both stimulation of Epac by 8-p-methoxyphenylthon-2'-O-methyl-cAMP and overexpression of Epac significantly increased DNA fragmentation and TUNEL (terminal deoxynucleotidyltransferase-mediated biotin nick end-labeling)-positive cell counts in mouse cortical neurons but not in cardiac myocytes. In contrast, stimulation of protein kinase A increased apoptosis in cardiac myocytes but not in neuronal cells. In cortical neurons the expression of the Bcl-2 interacting member protein (Bim) was increased by stimulation of Epac at the transcriptional level and was decreased in mice with genetic disruption of Epac1. Epac-induced neuronal apoptosis was attenuated by the silencing of Bim. Furthermore, Epac1 disruption in vivo abolished the 3-nitropropionic acid-induced neuronal apoptosis that occurs in wild-type mice. These results suggest that Epac induces neuron-specific apoptosis through increasing Bim expression. Because the disruption of Epac exerted a protective effect on neuronal apoptosis in vivo, the inhibition of Epac may be a consideration in designing a therapeutic strategy for the treatment of neurodegenerative diseases.

SUBMITTER: Suzuki S

PROVIDER: S-EPMC2911347 | biostudies-other | 2010 Jul

REPOSITORIES: biostudies-other

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Differential roles of Epac in regulating cell death in neuronal and myocardial cells.

Suzuki Sayaka S Yokoyama Utako U Abe Takaya T Kiyonari Hiroshi H Yamashita Naoya N Kato Yuko Y Kurotani Reiko R Sato Motohiko M Okumura Satoshi S Ishikawa Yoshihiro Y

The Journal of biological chemistry 20100601 31

Cell survival and death play critical roles in tissues composed of post-mitotic cells. Cyclic AMP (cAMP) has been known to exert a distinct effect on cell susceptibility to apoptosis, protecting neuronal cells and deteriorating myocardial cells. These effects are primarily studied using protein kinase A activation. In this study we show the differential roles of Epac, an exchange protein activated by cAMP and a new effector molecule of cAMP signaling, in regulating apoptosis in these cell types. ...[more]

PMID: 20516079

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Project description:SAFB1 is a RNA binding protein implicated in the regulation of multiple cellular processes such as the regulation of transcription, stress response, DNA repair and RNA processing. To gain further insight into SAFB1 function we used iCLIP and mapped its interaction with RNA on a genome wide level.iCLIP analysis found SAFB1 binding was enriched, specifically in exons, ncRNAs, 3' and 5' untranslated regions. SAFB1 was found to recognise a purine-rich GAAGA motif with the highest frequency and it is therefore likely to bind core AGA, GAA, or AAG motifs. Confirmatory RT-PCR experiments showed that the expression of coding and non-coding genes with SAFB1 cross-link sites was altered by SAFB1 knockdown. For example, we found that the isoform-specific expression of neural cell adhesion molecule (NCAM1) and ASTN2 was influenced by SAFB1 and that the processing of miR-19a from the miR-17-92 cluster was regulated by SAFB1. These data suggest SAFB1 may influence alternative splicing and, using an NCAM1 minigene, we showed that SAFB1 knockdown altered the expression of two of the three NCAM1 alternative spliced isoforms. However, when the AGA, GAA, and AAG motifs were mutated, SAFB1 knockdown no longer mediated a decrease in the NCAM1 9-10 alternative spliced form. To further investigate the association of SAFB1 with splicing we used exon array analysis and found SAFB1 knockdown mediated the statistically significant up- and downregulation of alternative exons. Further analysis using RNAmotifs to investigate the frequency of association between the motif pairs (AGA followed by AGA, GAA or AAG) and alternative spliced exons found there was a highly significant correlation with downregulated exons. Together, our data suggest SAFB1 will play an important physiological role in the central nervous system regulating synaptic function. We found that SAFB1 regulates dendritic spine density in hippocampal neurons and hence provide empirical evidence supporting this conclusion.iCLIP showed that SAFB1 has previously uncharacterised specific RNA binding properties that help coordinate the isoform-specific expression of coding and non-coding genes. These genes regulate splicing, axonal and synaptic function, and are associated with neuropsychiatric disease, suggesting that SAFB1 is an important regulator of key neuronal processes.

Dataset Information

Differential roles of Epac in regulating cell death in neuronal and myocardial cells.

Publications

Differential roles of Epac in regulating cell death in neuronal and myocardial cells.

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