Abstract
Up-regulation of the apoptosis-regulatory gene Mcl-1 (myeloid cell leukemia-1) occurs in different cancer types and is linked with drug resistance to cancer therapies. It is well known that Mcl-1 pre-mRNA undergoes alternative splicing events to produce two functionally distinct proteins, Mcl-1(S) (pro-apoptotic) and Mcl-l(L) (anti-apoptotic); the latter isoform is predominant in different cancers including breast and ovarian cancer cells. In the present study we report that the RNA-binding protein (RBP) and proto-oncogene SRSF1 (serine and arginine-rich splicing factor 1) influences splicing of Mcl-1 in both MCF-7 and MDA-MB-231 breast cancer cells and JAR choriocarcinoma cells; we also show for the first time that another RBP SRSF5 affects splicing of Mcl-1 in the MCF-7 cells. Moreover, we report that SRSF1 is involved in other aspects of Mcl-1 regulation with knockdown of SRSF1, by RNAi, resulting in a significant decrease in Mcl-1 protein levels in MCF-7 cells but an increase in JAR cells, respectively, by potentially affecting protein stability and translation of Mcl-l. The key findings from this study highlight the importance of the cellular context of different cancer cells for the function of multifunctional RBPs like SRSF1 and have implications for therapeutic approaches employed to target Mcl-1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics*
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Alternative Splicing*
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Apoptosis
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Blotting, Western
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Proliferation
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Choriocarcinoma / genetics*
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Choriocarcinoma / metabolism
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Choriocarcinoma / pathology
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Female
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Humans
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Myeloid Cell Leukemia Sequence 1 Protein
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Proto-Oncogene Mas
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Proto-Oncogene Proteins c-bcl-2 / genetics*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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RNA-Binding Proteins / antagonists & inhibitors
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism*
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Serine-Arginine Splicing Factors
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Tumor Cells, Cultured
Substances
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MAS1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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Nuclear Proteins
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Proto-Oncogene Mas
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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RNA, Small Interfering
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RNA-Binding Proteins
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Serine-Arginine Splicing Factors
Grants and funding
This work was supported by a grant awarded from the JGW Patterson Foundation and supplementary funding from the Newcastle Healthcare Charity (RVI/NGH) and Newcastle upon Tyne Hospitals NHS Charity (FH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.