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PXD022333

PXD022333 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleA novel class of CLK kinases inhibitors that target SRSF10 and promote p53mediated cytotoxicity on human colorectal cancer cells
DescriptionThe elevated expression of the splicing regulator SRSF10 in metastatic colorectal cancer (CRC) stimulates the production of the pro-tumorigenic Bclaf1-L splice variant. We discovered a group of small molecules with an aminothiazole carboxamide core (GPS167, GPS192 and others) that decrease production of Bclaf1-L. While additional alternative splicing events regulated by SRSF10 are affected by GPS167/192 in HCT116 cells (e.g., in MDM4, WTAP, SLK1 and CLK1), other events are shifted in a SRSF10-independent manner (e.g., in MDM2, NAB2 and TRA2A). GPS167/192 increased the interaction of SRSF10 with the CLK1 and CLK4 kinases, leading us to show that GPS167/192 are CLK kinase inhibitors preferentially impacting the activity of SRSF10. Notably, GPS167 impairs the growth of CRC cell lines and organoids, inhibits anchorage-independent colony formation, cell migration, and promotes cytoxicity that requires SRSF10 and p53. In contrast, GPS167 only minimally affects normal colonocytes and normal colorectal organoids. Thus, GPS167 reprograms the tumorigenic activity of SRSF10 in CRC cells to elicit p53-dependent apoptosis.
HostingRepositoryPRIDE
AnnounceDate2021-09-09
AnnouncementXMLSubmission_2021-09-09_13:33:37.056.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterLulzim Shkreta
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListphosphorylated residue
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02020-11-04 01:38:24ID requested
12021-09-09 13:33:37announced
Publication List
Sohail M, Shkreta L, Toutant J, Rabea S, Babeu JP, Huard C, Coulombe-Huntington J, Delannoy A, Placet M, Geha S, Gendron FP, Boudreau F, Tyers M, Grierson DS, Chabot B, A novel class of inhibitors that target SRSF10 and promote p53-mediated cytotoxicity on human colorectal cancer cells. NAR Cancer, 3(2):zcab019(2021) [pubmed]
Keyword List
submitter keyword: CLK Kinases inhibitor, SRSF10, human colorectal cancer cells
Contact List
Benoit Chabot
contact affiliationDepartment of Microbiology and Infectious Diseases.Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
contact emailBenoit.Chabot@USherbrooke.ca
lab head
Lulzim Shkreta
contact affiliationUniversite de Sherbrooke
contact emailLulzim.Shkreta@USherbrooke.ca
dataset submitter
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