Oxidative stress-inducible truncated serine/arginine-rich splicing factor 3 regulates interleukin-8 production in human colon cancer cells

Abstract

Serine/arginine-rich splicing factor 3 (SRSF3) is a member of the SR protein family and plays wide-ranging roles in gene expression. The human SRSF3 gene generates two alternative splice transcripts, a major mRNA isoform (SRSF3-FL) encoding functional full-length protein and a premature termination codon (PTC)-containing isoform (SRSF3-PTC). The latter is degraded through nonsense-mediated mRNA decay (NMD). Treatment of a human colon cancer cell line (HCT116) with 100 μM sodium arsenite increased SRSF3-PTC mRNA levels without changing SRSF3-FL mRNA levels. A chemiluminescence-based NMD reporter assay system demonstrated that arsenite treatment inhibited NMD activity and increased SRSF3-PTC mRNA levels in the cytoplasm, facilitating translation of a truncated SRSF3 protein (SRSF3-TR) from SRSF3-PTC mRNA. SRSF3-TR lacked two-thirds of the Arg/Ser-rich (RS) domain whose phosphorylation state is known to be crucial for subcellular distribution. SRSF3-FL was localized in the nucleus, while overexpressed SRSF3-TR was diffusely distributed in the cytoplasm and the nucleus. A part of SRSF3-TR was also associated with stress granules in the cytoplasm. Interestingly, treatment of HCT116 cells with a small interference RNA specifically targeting SRSF3-PTC mRNA significantly attenuated arsenite-stimulated induction of c-JUN protein, its binding activity to the AP-1 binding site (-126 to 120 bp) in the interleukin (IL)-8 gene promoter, and AP-1 promoter activity, resulting in significant reduction of arsenite-stimulated IL-8 production. Our results suggest that SRSF3-TR may function as a positive regulator of oxidative stress-initiated inflammatory responses in colon cancer cells.

Degradation of splicing factor SRSF3 contributes to progressive liver disease

“…When broken down by category, cassette exons and alternative 3′ and 5′ splice sites again made up the majority of the significant AS events ( Figure 2H). Interestingly, the HFD RNA had a much higher proportion of intron retention events than the SRSF3-KO RNA, which possibly indicated alterations in other splicing factors (28). When the genes subject to AS were compared, 15% of the genes altered by HFD (56 of 368) were also SRSF3 dependent ( Figure 2I) that represented a significant enrichment (P < 0.05 by Fisher's exact test).…”

“…We also investigated the effect of HFD and Western diet on Srsf3 mRNA expression. The Srsf3 gene generates 2 mRNA transcripts through alternative splicing of exon 4; the major transcript (Srsf3-202) skips exon 4 and encodes the full-length SRSF3 protein (Srsf3-FL), and the minor transcript (Srsf3-201) includes exon 4 and contains a premature termination codon (PTC) causing the mRNA to be degraded by nonsense-mediated decay (Srsf3-PTC) (3,28,29). RNA from normal, NAFLD, NASH, and cirrhosis liver samples showed higher expression of SRSF3-FL than SRSF3-PTC (Supplemental Figure 4A).…”

New IL-15 receptor-α splicing variants identified in intestinal epithelial Caco-2 cells

“…32 Interestingly, other alternative splicing variants from cytokine receptors have already been associated to IBD, 33,34 and with human colon cancer IL-8 expression. 35 Moreover, gene expression and alternative splicing are not only dependent on the tissue, but also on epigenetic factors, 21 and changes in the expression of intestinal genes have been found to be related to the inhibition of histone deacetylation 36 and an increased DNA methylation, 37 Several epigenetic mechanisms have been found to be differently regulated in the intestinal mucosa of patients with celiac disease, IBD and colorectal cancer. [38][39][40] Interestingly, the IL-15 gene is hypomethylated in IBD.…”

Nonclassical nuclear localization signals mediate nuclear import of CIRBP

“…As both TNPO1 and TNPO3 suppress phase separation of CIRBP and its localization in SGs, they might be involved in regulating CIRBP function in cell adaption to stress, possibly allowing release of CIRBP-bound RNA targets and making them available for the translation machinery. Other than CIRBP, several proteins that contain an NLS for TNPO3 localize to cellular condensates, including ASF/SF2 (66) and SRSF3 (67,68) in humans and several serine/arginine-rich proteins in Caenorhabditis elegans (69), suggesting a general role of TNPO3 in chaperoning its cargo RBPs. Numerous studies have underscored a critical role of SGs in neurodegenerative disorders (70)(71)(72).…”