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

被引:43
作者
Shimoni-Sebag, Ariel [1 ]
Lebenthal-Loinger, Ilana [1 ]
Zender, Lars [2 ]
Karni, Rotem [1 ]
机构
[1] Hebrew Univ Jerusalem, Hadassah Med Sch, Inst Med Res Israel Canada, Dept Biochem & Mol Biol, IL-91120 Jerusalem, Israel
[2] Univ Tubingen Hosp, Div Mol Oncol Solid Tumors, Dept Internal Med 1, D-72076 Tubingen, Germany
关键词
RNA RECOGNITION MOTIFS; SR PROTEIN FAMILY; MESSENGER-RNA; TUMOR-SUPPRESSOR; FACTOR SF2/ASF; INHIBITION; MUTATIONS; PHOSPHORYLATION; PROLIFERATION; APOPTOSIS;
D O I
10.1093/carcin/bgt247
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 structurefunction 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-MEK-ERK pathway and to promote cellular transformation.
引用
收藏
页码:2498 / 2504
页数:7
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