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Functional consequence of the splicing factor SF1 inhibition in leukemic cell line

Grant number: 16/19658-4
Support type:Scholarships in Brazil - Master
Effective date (Start): October 01, 2016
Effective date (End): September 30, 2018
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Leticia Fröhlich Archangelo
Grantee:Illy Enne Gomes Pereira
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:14/01458-3 - Defining the functional role of the splicing factor regulator (KIS) during leukemogenesis using a murine bone marrow transplantion model, AP.JP

Abstract

The splicing factor SF1 recognizes the 3 'regions of the introns during the early stages of spliceosome formation, but is not required for general splicing of all pre-mRNA in eukaryotic cells. Thus, SF1 targets a subset of pre-mRNAs, acting as an alternative splicing factor. Besides SF1 function in splicing, its role in tumorigenesis has also been described. SF1 can act either as an oncogene or as a tumor suppressor, depending on cell type and tissue analyzed. Recent studies demonstrated the occurrence of SF1 mutations in hematologic diseases, but the functional consequence of these mutations is not determined. It has been suggested that these mutations would impair the 3 'end intron recognition, leading to production of aberrant transcripts. Currently, it is argued that these changes in the splicing process may represent a new mechanism in leukemogenesis. Therefore, studying the functional consequence of SF1 inhibition in hematopoietic cells would provide further insight into its function in hematological neoplasms. SF1 knockdown will allow us to analyze the effects of its depletion during differentiation and proliferation of leukemic cell lines, and also to evaluate its contribution pre-mRNA processing in these cells. First we will evaluate the SF1 gene and protein expression in different leukemic cell lines in order to choose the more appropriate cell line for lentivirus-mediated inhibition of SF1. SF1 silenced cells will be used for functional in vitro and in vivo assays such as proliferation, cell cycle, apoptosis, migration, colony forming unit and tumor growth. This work is part of other projects from our group involving the protein kinase KIS, which interacts with and phosphorylates SF1. Hence, we aim to investigate the emerging role of the spliceosome machinery in the biogenesis of hematologic disorders. (AU)