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Regulation of the Alternative Splicing of Tumor-Related RAC1B by Signal Transdcution pathways

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dc.contributor.authorGonçalves, Vânia
dc.contributor.authorMatos, Paulo
dc.contributor.authorPereira, Joana
dc.contributor.authorHenriques, Andreia
dc.contributor.authorJordan, Peter
dc.date.accessioned2020-05-19T12:22:37Z
dc.date.available2020-11-14T01:30:15Z
dc.date.issued2019
dc.description.abstractIntroduction: 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. Materials and 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 and Discussion: 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, decreasing SRPK1 nuclear translocation and inhibiting RAC1B overexpression. Together, our results demonstrate that oncogenic signal transduction pathways deregulate alternative splicing and this may be drug revertable.pt_PT
dc.description.sponsorshipFCT; BioISI; Maratona da Saúdept_PT
dc.description.versionN/Apt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/6702
dc.language.isoengpt_PT
dc.subjectColorectal Cancerpt_PT
dc.subjectAlternative Splicingpt_PT
dc.subjectSignal transductionpt_PT
dc.subjectVias de Transdução de Sinal e Patologias Associadaspt_PT
dc.titleRegulation of the Alternative Splicing of Tumor-Related RAC1B by Signal Transdcution pathwayspt_PT
dc.typeconference object
dspace.entity.typePublication
oaire.citation.conferencePlacePortugalpt_PT
oaire.citation.title23nd Annual Meeting of the Portuguese Society of Human Genetics, Coimbra, 14-16 Novembro 2019pt_PT
oaire.citation.titleVIII National RNA Meeting 2019, FCUP, Porto, 24-25 January 2019
rcaap.rightsopenAccesspt_PT
rcaap.typeconferenceObjectpt_PT

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