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Stress-responsive maturation of Clk1/4 pre-mRNAs promotes phosphorylation of SR splicing factor.

ABSTRACT: It has been assumed that premessenger ribonucleic acids (RNAs; pre-mRNAs) are spliced cotranscriptionally in the process of gene expression. However, in this paper, we report that splicing of Clk1/4 mRNAs is suspended in tissues and cultured cells and that intermediate forms retaining specific introns are abundantly pooled in the nucleus. Administration of the Cdc2-like kinase-specific inhibitor TG003 increased the level of Clk1/4 mature mRNAs by promoting splicing of the intron-retaining RNAs. Under stress conditions, splicing of general pre-mRNAs was inhibited by dephosphorylation of SR splicing factors, but exposure to stresses, such as heat shock and osmotic stress, promoted the maturation of Clk1/4 mRNAs. Clk1/4 proteins translated after heat shock catalyzed rephosphorylation of SR proteins, especially SRSF4 and SRSF10. These findings suggest that Clk1/4 expression induced by stress-responsive splicing serves to maintain the phosphorylation state of SR proteins.

SUBMITTER: Ninomiya K

PROVIDER: S-EPMC3187705 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Stress-responsive maturation of Clk1/4 pre-mRNAs promotes phosphorylation of SR splicing factor.

Ninomiya Kensuke K Kataoka Naoyuki N Hagiwara Masatoshi M

The Journal of cell biology 20110926 1

It has been assumed that premessenger ribonucleic acids (RNAs; pre-mRNAs) are spliced cotranscriptionally in the process of gene expression. However, in this paper, we report that splicing of Clk1/4 mRNAs is suspended in tissues and cultured cells and that intermediate forms retaining specific introns are abundantly pooled in the nucleus. Administration of the Cdc2-like kinase-specific inhibitor TG003 increased the level of Clk1/4 mature mRNAs by promoting splicing of the intron-retaining RNAs. ...[more]

PMID: 21949414

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Project description:Although endometrial cancer is the most common cancer of the female reproductive tract, we have little understanding of what controls endometrial cancer beyond the transcriptional effects of steroid hormones such as estrogen. As a result, we have limited therapeutic options for the ~62,000 women diagnosed with endometrial cancer each year in the United States. Here, in an attempt to identify new prognostic and therapeutic targets, we focused on a new area for this cancer-alternative mRNA splicing-and investigated whether splicing factor, SF3B1, plays an important role in endometrial cancer pathogenesis. Using a tissue microarray, we found that human endometrial tumors expressed more SF3B1 protein than non-cancerous tissues. Furthermore, SF3B1 knockdown reduced in vitro proliferation, migration, and invasion of the endometrial cancer cell lines Ishikawa and AN3CA. Similarly, the SF3B1 inhibitor, Pladienolide-B (PLAD-B), reduced the Ishikawa and AN3CA cell proliferation and invasion in vitro. Moreover, PLAD-B reduced tumor growth in an orthotopic endometrial cancer mouse model. Using RNA-Seq approach, we identified ~2000 differentially expressed genes (DEGs) with SF3B1 knockdown in endometrial cancer cells. Additionally, alternative splicing (AS) events analysis revealed that SF3B1 depletion led to alteration in multiple categories of AS events including alternative exon skipping (ES), transcript start site usage (TSS), and transcript termination site (TTS) usage. Subsequently, bioinformatics analysis showed KSR2 as a potential candidate for SF3B1-mediated functions in endometrial cancer. Specifically, loss of SF3B1 led to decrease in KSR2 expression, owing to reduced maturation of KSR2 pre-mRNA to a mature RNA. Importantly, we found rescuing the KSR2 expression with SF3B1 knockdown partially restored the cell growth of endometrial cancer cells. Taken together, our data suggest that SF3B1 plays a crucial oncogenic role in the tumorigenesis of endometrial cancer and hence may support the development of SF3B1 inhibitors to treat this disease.

Dataset Information

Stress-responsive maturation of Clk1/4 pre-mRNAs promotes phosphorylation of SR splicing factor.

Publications

Stress-responsive maturation of Clk1/4 pre-mRNAs promotes phosphorylation of SR splicing factor.

Similar Datasets

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