Manipulation of alternative splicing by a newly developed inhibitor of Clks

Muraki, M., Ohkawara, B., Hosoya, T., Onogi, H., Koizumi, J., Koizumi, T., Sumi, K., Jun-ichiro, Y., Murray, M. V., Kimura, H., Furuichi, K., Shibuya, H., Krainer, A. R., Suzuki, M., Hagiwara, M. (2004) Manipulation of alternative splicing by a newly developed inhibitor of Clks. Journal of Biological Chemistry, 279 (23). pp. 24246-24254. ISSN 0021-9258

URL: http://www.ncbi.nlm.nih.gov/pubmed/15010457
DOI: 10.1074/jbc.M314298200

Abstract

The regulation of splice site usage provides a versatile mechanism for controlling gene expression and for the generation of proteome diversity, playing an essential role in many biological processes. The importance of alternative splicing is further illustrated by the increasing number of human diseases that have been attributed to mis-splicing events. Appropriate spatial and temporal generation of splicing variants demands that alternative splicing be subjected to extensive regulation, similar to transcriptional control. The Clk (Cdc2-like kinase) family has been implicated in splicing control and consists of at least four members. Through extensive screening of a chemical library, we found that a benzothiazole compound, TG003, had a potent inhibitory effect on the activity of Clk1/Sty. TG003 inhibited SF2/ASF-dependent splicing of beta-globin pre-mRNA in vitro by suppression of Clk-mediated phosphorylation. This drug also suppressed serine/arginine-rich protein phosphorylation, dissociation of nuclear speckles, and Clk1/Sty-dependent alternative splicing in mammalian cells. Consistently, administration of TG003 rescued the embryonic defects induced by excessive Clk activity in Xenopus. Thus, TG003, a novel inhibitor of Clk family will be a valuable tool to dissect the regulatory mechanisms involving serine/arginine-rich protein phosphorylation signaling pathways in vivo, and may be applicable for the therapeutic manipulation of abnormal splicing.

Item Type: Paper
Uncontrolled Keywords: POLYMERASE-II TRANSCRIPTION Polymerase II transcription Polymerase-II SPINAL MUSCULAR-ATROPHY spinal muscular atrophy PROTEIN-KINASE protein kinase SR PROTEINS SR proteins SERINE-RICH serine-rich IN-VIVO in-vivo DROSOPHILA-MELANOGASTER Drosophila Melanogaster NUCLEAR nuclear speckles SPECKLES HUMAN-DISEASE human disease CELL-CYCLE cell cycle
Subjects: bioinformatics > genomics and proteomics > annotation > gene expression profiling annotation
CSHL Authors:
Communities: CSHL labs > Krainer lab
Depositing User: CSHL Librarian
Date Deposited: 31 Jan 2012 16:13
Last Modified: 09 Apr 2014 16:46
Related URLs:
URI: http://repository.cshl.edu/id/eprint/22444

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