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The Journal of Neuroscience, July 15, 2002, 22(14):5889-5899
Ischemia Induces a Translocation of the Splicing Factor tra2- 1
and Changes Alternative Splicing Patterns in the Brain
Rosette
Daoud1,
Günter
Mies2,
Agata
Smialowska1,
Laszlo
Oláh1,
Konstantin-Alexander
Hossmann2, and
Stefan
Stamm1
1 Institute of Biochemistry, University of
Erlangen-Nurenberg, 91054 Erlangen, Germany, and
2 Max-Planck-Institute for Neurological Research,
50931 Köln, Germany
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- 1 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 tra2-1. In addition, several of the proteins binding to
tra2-1, 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.
Key words:
alternative pre-mRNA processing; SR proteins; ischemia; phosphorylation; calcium; stroke
Copyright © 2002 Society for Neuroscience 0270-6474/02/22145889-11$05.00/0
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