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Regulation of Mcl-1 by SRSF1 and SRSF5 in cancer cells

Lookup NU author(s): Dr Hannah Gautrey, Professor Alison Tyson-Capper

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Abstract

Up-regulation of the apoptosis-regulatory gene Mcl-1 (myeloid cell leukemia-1) has been observed 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 RBP (RNA-binding protein) and proto-oncogene SRSF1 (serine and arginine-rich splicing factor 1) influences splicing of Mcl-1 in both MCF-7 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 both 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 metadata

Author(s): Gautrey HL, Tyson-Capper AJ

Publication type: Article

Publication status: Published

Journal: PLoS One

Year: 2012

Volume: 7

Issue: 12

Print publication date: 17/12/2012

Date deposited: 08/01/2013

ISSN (electronic): 1932-6203

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.pone.0051497

DOI: 10.1371/journal.pone.0051497

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