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

Ariel Shimoni-Sebag1, Ilana Lebenthal-Loinger, Lars Zender

  • 1Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Ein Karem, Jerusalem 91120, Israel and.

Carcinogenesis
|July 12, 2013
PubMed

Insights

The RNA recognition motif 1 (RRM1) domain of serine and arginine splicing factor 1 (SRSF1) is crucial for its oncogenic activity. This domain activates the B-Raf-MEK-ERK pathway, promoting cellular transformation in cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Alternative splicing regulators are increasingly recognized for their roles in cancer development.
  • Serine and arginine splicing factor 1 (SRSF1) is a proto-oncogene implicated in breast cancer.
  • Mechanisms linking oncogenic splicing factors to cellular transformation remain largely unknown.

Purpose of the Study:

  • To investigate the structure-function relationship of SRSF1 in cellular transformation.
  • To identify the specific domains of SRSF1 responsible for its oncogenic activity.
  • To elucidate the signaling pathways regulated by SRSF1 during transformation.

Main Methods:

  • Structure-function analysis of SRSF1 domains.
  • Assessment of SRSF1 splicing activity on endogenous targets.
  • Analysis of B-Raf expression and MEK-ERK pathway activation.
  • Pharmacological inhibition of MEK1 to assess its role in SRSF1-mediated transformation.

Main Results:

  • The RNA recognition motif 1 (RRM1) domain of SRSF1 is essential for its oncogenic activity.
  • Deletion of RRM1 impaired SRSF1's splicing activity on certain targets.
  • SRSF1 upregulates B-Raf expression and activates the MEK-ERK signaling pathway.
  • RRM1 is required for SRSF1-mediated activation of the B-Raf-MEK-ERK pathway.
  • Inhibition of MEK1 significantly reduced SRSF1-induced cellular transformation.

Conclusions:

  • The RRM1 domain of SRSF1 is critical for its ability to activate the Raf-MEK-ERK pathway.
  • SRSF1-mediated activation of the Raf-MEK-ERK pathway contributes significantly to cellular transformation.
  • The RRM1 domain, when tethered to the RS domain, is sufficient to promote cellular transformation by activating this pathway.

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