RRM1 domain of the splicing oncoprotein SRSF1 is required for MEK1-MAPK-ERK activation and cellular transformation

Ariel Shimoni-Sebag, Ilana Lebenthal-Loinger, Lars Zender, Rotem Karni*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Alternative splicing regulators have emerged as new players in cancer development, modulating the activities of many tumor suppressors and oncogenes and regulating the signaling pathways. However, little is known about the mechanisms by which these oncogenic splicing factors lead to cellular transformation. We have shown previously that the splicing factor serine and arginine splicing factor 1 (SRSF1; SF2/ASF) is a proto-oncogene, which is amplified in breast cancer and transforms immortal cells when overexpressed. In this study, we performed a structure-function analysis of SRSF1 and found that the RNA recognition motif 1 (RRM1) domain is required for its oncogenic activity. Deletion of RRM1 eliminated the splicing activity of SRSF1 on some of its endogenous targets. Moreover, we found that SRSF1 elevates the expression of B-Raf and activates the mitogen-activated protein kinase kinase (MEK) extracellular signal-regulated kinase (ERK) pathway and that RRM1 is required for this activation as well. B-Raf-MEK-ERK activation by SRSF1 contributes to transformation as pharmacological inhibition of MEK1 inhibits SRSF1-mediated transformation. In conclusion, RRM1 of SRSF1 is both required (and when tethered to the RS domain) also sufficient to activate the Raf-MEKERK pathway and to promote cellular transformation.

Original languageAmerican English
Pages (from-to)2498-2504
Number of pages7
JournalCarcinogenesis
Volume34
Issue number11
DOIs
StatePublished - Nov 2013

Bibliographical note

Funding Information:
Israeli Science Foundation (ISF 780/08 and 1290/12 to R.K.); MINERVA Stiftung ARCHES Award from Federal Ministry of Education and Research (BMBF), Germany (to R.K. and L.Z.)

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