Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster display session

3659 - Signal Transduction Pathways Regulating Alternative Splicing of Tumor-Related RAC1b

Date

11 Sep 2017

Session

Poster display session

Presenters

Vânia Gonçalves

Citation

Annals of Oncology (2017) 28 (suppl_5): v1-v21. 10.1093/annonc/mdx361

Authors

V. Gonçalves, P. Matos, A.A. Henriques, J. Pereira, P. Jordan

Author affiliations

  • Human Genetics Department, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 - Lisboa/PT
More

Resources

Abstract 3659

Background

In colon cancer distinct genetic subtypes have been described, one of which involves overexpression of RAC1b, a variant generated by alternative splicing. Aberrant splicing is known to occur in cancer and can be caused by mutation in a gene or splicing factor but also represents a dynamic response to oncogene-induced cellular signaling and in this case it may be pharmacologically targeted. Here we explore how signaling pathways are involved in the deregulation of alternative RAC1b splicing in colorectal tumor cells.

Methods

HT29 colorectal cells represent serrated colorectal tumors with BRAF gene mutation V600E in one allele and RAC1b overexpression. Cells were transfected with shRNA vectors directed against target candidate protein kinase transcripts and their effects on RAC1b levels analyzed 24h later by Western Blot and qRT-PCR. Treatment with kinase inhibitors or anti-inflammatory drugs was performed 24h prior to cell lysis.

Results

Two kinases, SRPK1 and GSK3β, were found required to sustain RAC1b levels and both were shown to act upon the phosphorylation of splicing factor SRSF1, which binds to and promotes the inclusion of the alternative exon in RAC1b. SRPK1 knockdown or pharmacological inhibition reduced SRSF1 phosphorylation decreasing its nuclear translocation and concomitantly RAC1b splicing. The same regulatory pathway was also found to be controlled by GSK3β. Interestingly, GSK3β phosphorylation was identified to serve as target for the anti-inflammatory drug ibuprofen, which inhibits RAC1b overexpression.

Conclusions

Together, our results demonstrate that oncogenic signal transduction pathways deregulate alternative splicing and this may be drug revertable.

Clinical trial identification

Legal entity responsible for the study

Peter Jordan

Funding

Fundação para a Ciência e Tecnologia

Disclosure

All authors have declared no conflicts of interest.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.