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1.  Splicing factor SRSF6 promotes hyperplasia of sensitized skin 
Summary
Many biological processes involve gene-expression regulation by alternative splicing. Here, we identify the splicing factor SRSF6 as a regulator of wound healing and tissue homeostasis in skin. We show that SRSF6 is a proto-oncogene that is frequently overexpressed in human skin cancer. Overexpressing it in transgenic mice induces hyperplasia of sensitized skin and promotes aberrant alternative splicing. We identify 139 target genes of SRSF6 in skin, and show that this SR protein binds to alternative exons of the extracellular-matrix protein tenascin C pre-mRNA, promoting the expression of isoforms characteristic of invasive and metastatic cancer in a cell-type-independent manner. SRSF6 overexpression additionally results in depletion of Lgr6+ stem cells, and excessive keratinocyte proliferation and response to injury. Furthermore, the effects of SRSF6 in wound healing assayed in vitro depend on the TNC isoforms. Thus, abnormal SR-protein expression can perturb tissue homeostasis.
doi:10.1038/nsmb.2756
PMCID: PMC4118672  PMID: 24440982
2.  SF2/ASF Autoregulation Involves Multiple Layers of Post-transcriptional and Translational Control 
SF2/ASF is a prototypical SR protein, with important roles in splicing and other aspects of mRNA metabolism. SFRS1 (SF2/ASF) is a potent proto-oncogene with abnormal expression in many tumors. We found that SF2/ASF negatively autoregulates its expression to maintain homeostatic levels. We characterized six SF2/ASF alternatively spliced mRNA isoforms: the major isoform encodes full-length protein, whereas the others are either retained in the nucleus or degraded by NMD. Unproductive splicing accounts for only part of the autoregulation, which occurs primarily at the translational level. The effect is specific to SF2/ASF and requires RRM2. The ultraconserved 3′UTR is necessary and sufficient for downregulation. SF2/ASF overexpression shifts the distribution of target mRNA towards mono-ribosomes, and translational repression is partly independent of Dicer and a 5′ cap. Thus, multiple post-transcriptional and translational mechanisms are involved in fine-tuning the expression of SF2/ASF.
doi:10.1038/nsmb.1750
PMCID: PMC2921916  PMID: 20139984
3.  THE SPLICING FACTOR SRSF1 REGULATES APOPTOSIS AND PROLIFERATION TO PROMOTE MAMMARY EPITHELIAL CELL TRANSFORMATION 
The splicing-factor oncoprotein SRSF1 (also known as SF2/ASF) is upregulated in breast cancers. We investigated SRSF1’s ability to transform human and mouse mammary epithelial cells in vivo and in vitro. SRSF1-overexpressing COMMA-1D cells formed tumors, following orthotopic transplantation to reconstitute the mammary gland. In 3-D culture, SRSF1-overexpressing MCF-10A cells formed larger acini than control cells, reflecting increased proliferation and delayed apoptosis during acinar morphogenesis. These effects required the first RNA-recognition motif and nuclear functions of SRSF1. SRSF1 overexpression promoted alternative splicing of BIM and BIN1 isoforms that lack pro-apoptotic functions and contribute to the phenotype. Finally, SRSF1 cooperated specifically with MYC to transform mammary epithelial cells, in part by potentiating eIF4E activation, and these cooperating oncogenes are significantly co-expressed in human breast tumors. Thus, SRSF1 can promote breast cancer, and SRSF1 itself or its downstream effectors may be valuable targets for therapeutics development.
doi:10.1038/nsmb.2207
PMCID: PMC3272117  PMID: 22245967
4.  Recognition of atypical 5' splice sites by shifted base-pairing to U1 snRNA 
Accurate pre-mRNA splicing is critical for gene expression. The 5' splice site (5' ss) — the highly diverse element at the 5' end of introns — is initially recognized via base-pairing to the 5' end of U1 small nuclear RNA (snRNA). However, many natural 5' ss have a very poor match to the consensus sequence, and are predicted to be very weak. Using genetic suppression experiments in human cells, we demonstrate that some atypical 5' ss are actually efficiently recognized by U1, in an alternative base-pairing register that is shifted by one nucleotide. These atypical 5' ss are phylogenetically widespread, and many of them are conserved. Moreover, shifted base-pairing provides an explanation for the effect of a 5' ss mutation associated with pontocerebellar hypoplasia. The unexpected flexibility in 5' ss/U1 base-pairing challenges an established paradigm, and has broad implications for splice-site prediction algorithms and gene-annotation efforts in genome projects.
doi:10.1038/nsmb.1546
PMCID: PMC2719486  PMID: 19169258

Results 1-4 (4)