TY - JOUR
T1 - Ischemia induces a translocation of the splicing factor tra2-β1 and changes alternative splicing patterns in the brain
AU - Daoud, Rosette
AU - Mies, Günter
AU - Smialowska, Agata
AU - Oláh, Laszlo
AU - Hossmann, Konstantin Alexander
AU - Stamm, Stefan
PY - 2002/7/15
Y1 - 2002/7/15
N2 - Alternative splice-site selection is regulated by the relative concentration of individual members of the serine-arginine family of proteins and heterogeneous nuclear ribonucleoproteins. Most of these proteins accumulate predominantly in the nucleus, and a subset of them shuttles continuously between nucleus and cytosol. We demonstrate that in primary neuronal cultures, a rise in intracellular calcium concentration induced by thapsigargin leads to a translocation of the splicing regulatory protein tra2-β1 and a consequent change in splice-site selection. To investigate this phenomenon under physiological conditions, we used an ischemia model. Ischemia induced in the brain causes a cytoplasmic accumulation and hyperphosphorylation of tra2-β1. In addition, several of the proteins binding to tra2-β1, such as src associated in mitosis 68 and serine/arginine-rich proteins, accumulate in the cytosol. Concomitant with this subcellular relocalization, we observed a change in alternative splice-site usage of the ICH-1 gene. The increased usage of its alternative exons is in agreement with previous studies demonstrating its repression by a high concentration of proteins with serine/arginine-rich domains. Our findings suggest that a change in the calcium concentration associated with ischemia is part of a signaling event, which changes pre-mRNA splicing pathways by causing relocalization of proteins that regulate splice-site selection.
AB - Alternative splice-site selection is regulated by the relative concentration of individual members of the serine-arginine family of proteins and heterogeneous nuclear ribonucleoproteins. Most of these proteins accumulate predominantly in the nucleus, and a subset of them shuttles continuously between nucleus and cytosol. We demonstrate that in primary neuronal cultures, a rise in intracellular calcium concentration induced by thapsigargin leads to a translocation of the splicing regulatory protein tra2-β1 and a consequent change in splice-site selection. To investigate this phenomenon under physiological conditions, we used an ischemia model. Ischemia induced in the brain causes a cytoplasmic accumulation and hyperphosphorylation of tra2-β1. In addition, several of the proteins binding to tra2-β1, such as src associated in mitosis 68 and serine/arginine-rich proteins, accumulate in the cytosol. Concomitant with this subcellular relocalization, we observed a change in alternative splice-site usage of the ICH-1 gene. The increased usage of its alternative exons is in agreement with previous studies demonstrating its repression by a high concentration of proteins with serine/arginine-rich domains. Our findings suggest that a change in the calcium concentration associated with ischemia is part of a signaling event, which changes pre-mRNA splicing pathways by causing relocalization of proteins that regulate splice-site selection.
KW - Alternative pre-mRNA processing
KW - Calcium
KW - Ischemia
KW - Phosphorylation
KW - SR proteins
KW - Stroke
UR - http://www.scopus.com/inward/record.url?scp=0037101633&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037101633&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.22-14-05889.2002
DO - 10.1523/jneurosci.22-14-05889.2002
M3 - Article
C2 - 12122051
AN - SCOPUS:0037101633
SN - 0270-6474
VL - 22
SP - 5889
EP - 5899
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 14
ER -