Splicing factor SRSF3 represses the translation of programmed cell death 4 mRNA by associating with the 5′-UTR region

Abstract

Serine/arginine-rich splicing factor 3 (SRSF3), a member of the serine/arginine (SR)-rich family of proteins, regulates both alternative splicing of pre-mRNA and export of mature mRNA from the nucleus. Although its role in nuclear mRNA processing is well understood, the mechanism by which it alters the fate of cytoplasmic mRNA molecules remains elusive. Here, we provide evidence that SRSF3 not only regulates the alternative splicing pattern of programmed cell death 4 (PDCD4) mRNA, but also modulates its translational efficiency in the cytoplasm by lowering translation levels. We observed a marked increase in PDCD4 mRNA in translating polysome fractions upon silencing of SRSF3, and, conversely, ectopic overexpression of SRSF3 shifted PDCD4 mRNA into non-translating ribosomal fractions. In live cells, SRSF3 colocalized with PDCD4 mRNA in P-bodies (PBs), where translationally silenced mRNAs are deposited, and this localization was abrogated upon SRSF3 silencing. Furthermore, using two different reporter systems, we showed that SRSF3 interacts directly with PDCD4 mRNA and mediates translational repression by binding to the 5 0 -untranslated region (5 0 -UTR). In summary, our data suggest that the oncogenic potential of SRSF3 might be realized, in part, through the translational repression of PDCD4 mRNA.

Global Transcriptome Analysis of Formalin-Fixed Prostate Cancer Specimens Identifies Biomarkers of Disease Recurrence

“…Next, there is a set of cell cycle-related genes that includes CDC37L1, BTG2 (24), and SACM1L. In addition, there are several genes associated with apoptosis, PI3K, Insulin, metabolism, and steroid hormone signaling that includes IFT57 (34), ITPR1 (36), IGFBP3 (37), MEMO1 (38), FDPS (29), SRSF3 (39), MARCH5 (40), and MED4 (41–43). Another functional category contains genes associated with ribosomes and translation including RPL23AP53, SNORA20, and EIF2D.…”

Post-transcriptional Regulation of Programmed Cell Death 4 (PDCD4) mRNA by the RNA-binding Proteins Human Antigen R (HuR) and T-cell Intracellular Antigen 1 (TIA1)

“…With regard to post-transcriptional regulation of PDCD4, the only study beyond the extensive analysis of miR-21 (46,47), examined the regulation of the PDCD4 transcript by the splicing factor, SRSF3 (82). SRSF3 binds to the 5ЈUTR of the PDCD4 transcript and modulates splicing and translational efficiency (82). The work presented here, which provides evidence for two additional RNA-binding proteins that bind to and regulate the PDCD4 transcript, expands our understanding of the posttranscriptional regulation of PDCD4.…”

“…PDCD4 is regulated at the transcriptional level by the transcription factor, v-Myb (80), as well as by epigenetic regulation through DNA methylation (81). With regard to post-transcriptional regulation of PDCD4, the only study beyond the extensive analysis of miR-21 (46,47), examined the regulation of the PDCD4 transcript by the splicing factor, SRSF3 (82). SRSF3 binds to the 5ЈUTR of the PDCD4 transcript and modulates splicing and translational efficiency (82).…”

Serine/arginine-rich splicing factor 7 regulates p21-dependent growth arrest in colon cancer cells

“…SRSF7 recognizes CTEs of virus mRNAs through its RRM domain, and contributes to translational activation of these mRNAs as well as mRNA export of them (20,36). A subset of RNA-binding proteins, SRSF3 and RBM4, regulate translational activity of their targeted mRNAs through binding to 5'UTR of them (22,27). Like these RNA-binding proteins, SRSF7 might regulate translational activity of endogenous mRNAs, including CDKNA1A mRNA, as well as virus mRNAs.…”