SRSF1 (serine/arginine-rich splicing factor 1)

2011-11-01   Ruben Pio 

Department of Biochemistry, Division of Oncology (CIMA), University of Navarra, Pamplona, Spain

Identity

HGNC
LOCATION
17q22
LOCUSID
ALIAS
ASF,SF2,SF2p33,SFRS1,SRp30a
FUSION GENES

DNA/RNA

Atlas Image
Genomic structure of the SRSF1 gene. The black area indicates the coding sequence.

Description

The SRSF1 locus spans 6424 bp on the minus (-) strand of the long arm of chromosome 17 and is composed of 4 exons.

Transcription

ASF-1 (SF2) contains 4 exons (248 aa). Two additional cDNAs generated by alternative 3 splice-site use or by intron retention have been described and are designated ASF-2 (292 aa) and ASF-3 (201 aa), respectively. However, ASF/SF2 is the only isoform expressed at detectable levels.

Pseudogene

No known pseudogenes.

Proteins

Atlas Image
Schematic diagram of SF2/ASF protein. SF2/ASF has a modular structure with two RNA recognition motifs (RRM) that provide RNA-binding specificity and one arginine/serine-rich domain (RS), involved in protein-protein interactions that facilitate recruitment of the spliceosome. The RS domain acts also as a nuclear localization signal, controlling the subcellular localization of SF2/ASF. The protein can be phosphorilated in Ser residues in the C-terminal RS domain.

Description

248 amino acids, 28 kDa.

Expression

SF2/ASF is constitutively expressed in all cell types. However, there are differences in expression levels between cell types and organs. Moreover, in some pathological conditions the expression levels are altered.

Localisation

SF2/ASF is a shuttling protein with a high mobility between the nucleus and the cytoplasm. In the nucleus, SF2/ASF is concentrated in speckles and when transcription is activated it accumulates at the sites of transcription.

Function

SF2/ASF modulates both constitutive and alternative pre-mRNA splicing. The function of SF2/ASF in splicing depends on the pre-mRNA sequence and the cellular context. Cis-acting sequences and trans-acting factors modulate SF2/ASF activity. For example, SF2/ASF antagonizes the activity of hnRNP A/B proteins in splice site selection. An excess of hnRNP A1 favors distal 5 splice sites, whereas SF2/ASF promotes the use of proximal 5 splice sites.
SF2/ASF is also involved in transcription, mRNA export, nonsense-mediated mRNA decay, and translation.

Homology

SF2/ASF shares a high homology with other members of the SR family. SR proteins are conserved across vertebrates and invertebrates. They contain one or two copies of an RNA recognition motif (RRM) at the amino-terminus, spaced by a series of glycine residues that may form a flexible hinge, and a carboxy-terminal highly charged SR domain.

Mutations

Note

No mutations have been reported. Gene amplification has been found in some tumor types.

Implicated in

Entity name
Various cancers
Note
SF2/ASF acts as an oncogene.
SF2/ASF is upregulated in various human tumors, including lung, colon, kidney, liver, pancreas, ovary, cervix, and breast. Upregulation is sometimes associated with gene amplification. Overexpression of SF2/ASF is sufficient to transform immortal rodent fibroblasts.
mTORC1 activation may be essential for SF2/ASF-mediated transformation.
SF2/ASF-bound mRNAs recruit the mTOR kinase, resulting in the phosphorylation and release of 4E-BP, leading to translation initiation. Clinical tumors with SF2/ASF up-regulation may be especially sensitive to mTOR inhibitors.
Entity name
Non-small cell lung cancer (NSCLC)
Note
SF2/ASF and survivin expression are involved in non-small cell lung cancer progression.
SF2/ASF is overexpressed in lung cancer cell lines and human NSCLC specimens. SF2/ASF controls the expression of survivin through the activation of the mTOR pathway.
Entity name
Prostate cancer
Note
Cyclin D1b oncogene is induced by SF2/ASF.
SF2/ASF associates with cyclin D1b mRNA, an alternative splicing of the CCND1 transcript with enhanced oncogenic functions. SF2/ASF expression correlates with cyclin D1b in human prostate cancer.
Entity name
Cystic fibrosis
Note
Aberrant regulation of CFTR exon 9 alternative splicing by splicing factors may be associated with cystic fibrosis.
SF2/ASF binds to an intronic splicing silencer of exon 9 of CFTR and promotes exon exclusion.
Entity name
Cardiac remodeling
Note
SF2/ASF has a role in cardiac remodeling.
ASF/SF2 is a key regulator of alternative splicing events during postnatal heart remodeling.
Entity name
Retroviral splicing
Note
SF2/ASF regulates retroviral splicing.
SF2/ASF has been implicated in the regulation of retroviral splicing in Rous sarcoma virus, HIV-1 and HPV-16.
Entity name
Cell motility
Note
SF2/ASF activates epithelial to mesenchymal transition.
DeltaRon, a splicing isoform of the tyrosine kinase receptor Ron, increases motility. DeltaRon is generated by the skipping of exon 11. SF2/ASF, by controlling the production of DeltaRon, activates epithelial to mesenchymal transition, leading to cell locomotion.

Bibliography

Pubmed IDLast YearTitleAuthors
145557572003Processive phosphorylation of alternative splicing factor/splicing factor 2.Aubol BE et al
175766882007SR protein-mediated inhibition of CFTR exon 9 inclusion: molecular characterization of the intronic splicing silencer.Buratti E et al
94203311998A specific subset of SR proteins shuttles continuously between the nucleus and the cytoplasm.Cáceres JF et al
206827072010The oncoprotein SF2/ASF promotes non-small cell lung cancer survival by enhancing survivin expression.Ezponda T et al
193199562009Increased expression of cellular RNA-binding proteins in HPV-induced neoplasia and cervical cancer.Fay J et al
150695512004Expression of splicing factors in human ovarian cancer.Fischer DC et al
21637681990A protein factor, ASF, controls cell-specific alternative splicing of SV40 early pre-mRNA in vitro.Ge H et al
18552571991Primary structure of the human splicing factor ASF reveals similarities with Drosophila regulators.Ge H et al
163649132005Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene.Ghigna C et al
96302491998Regulated tissue-specific expression of antagonistic pre-mRNA splicing factors.Hanamura A et al
159072172005Dual effect of the SR proteins ASF/SF2, SC35 and 9G8 on HIV-1 RNA splicing and virion production.Jacquenet S et al
188321782008The splicing-factor oncoprotein SF2/ASF activates mTORC1.Karni R et al
173102522007The gene encoding the splicing factor SF2/ASF is a proto-oncogene.Karni R et al
23644341990The essential pre-mRNA splicing factor SF2 influences 5' splice site selection by activating proximal sites.Krainer AR et al
108932552000Reduced mobility of the alternate splicing factor (ASF) through the nucleoplasm and steady state speckle compartments.Kruhlak MJ et al
190614842009The SR protein family of splicing factors: master regulators of gene expression.Long JC et al
15311151992Regulation of alternative pre-mRNA splicing by hnRNP A1 and splicing factor SF2.Mayeda A et al
95841511998An RNA splicing enhancer-like sequence is a component of a splicing inhibitor element from Rous sarcoma virus.McNally LM et al
91681181997The dynamics of a pre-mRNA splicing factor in living cells.Misteli T et al
204605152010Identification of ASF/SF2 as a critical, allele-specific effector of the cyclin D1b oncogene.Olshavsky NA et al
107667632000Splicing factors induce cystic fibrosis transmembrane regulator exon 9 skipping through a nonevolutionary conserved intronic element.Pagani F et al
205193892010Multiple ASF/SF2 sites in the human papillomavirus type 16 (HPV-16) E4-coding region promote splicing to the most commonly used 3'-splice site on the HPV-16 genome.Somberg M et al
156524822005ASF/SF2-regulated CaMKIIdelta alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle.Xu X et al
15772771992SR proteins: a conserved family of pre-mRNA splicing factors.Zahler AM et al
75127321994The human splicing factor ASF/SF2 can specifically recognize pre-mRNA 5' splice sites.Zuo P et al

Other Information

Locus ID:

NCBI: 6426
MIM: 600812
HGNC: 10780
Ensembl: ENSG00000136450

Variants:

dbSNP: 6426
ClinVar: 6426
TCGA: ENSG00000136450
COSMIC: SRSF1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000136450ENST00000258962Q07955
ENSG00000136450ENST00000581979Q07955
ENSG00000136450ENST00000582730Q07955
ENSG00000136450ENST00000583741J3QQV5
ENSG00000136450ENST00000584668J3KSR8
ENSG00000136450ENST00000584773J3KTL2
ENSG00000136450ENST00000585096J3KSW7

Expression (GTEx)

0
50
100
150
200
250
300

Pathways

PathwaySourceExternal ID
SpliceosomeKEGGko03040
SpliceosomeKEGGhsa03040
Herpes simplex infectionKEGGko05168
Herpes simplex infectionKEGGhsa05168
Gene ExpressionREACTOMER-HSA-74160
RNA Polymerase II TranscriptionREACTOMER-HSA-73857
RNA Polymerase II Transcription TerminationREACTOMER-HSA-73856
Cleavage of Growing Transcript in the Termination RegionREACTOMER-HSA-109688
Processing of Capped Intron-Containing Pre-mRNAREACTOMER-HSA-72203
mRNA SplicingREACTOMER-HSA-72172
mRNA Splicing - Major PathwayREACTOMER-HSA-72163
mRNA Splicing - Minor PathwayREACTOMER-HSA-72165
mRNA 3'-end processingREACTOMER-HSA-72187
Transport of Mature Transcript to CytoplasmREACTOMER-HSA-72202
Transport of Mature mRNA derived from an Intron-Containing TranscriptREACTOMER-HSA-159236
IL-17 signaling pathwayKEGGko04657
IL-17 signaling pathwayKEGGhsa04657

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
173102522007The gene encoding the splicing factor SF2/ASF is a proto-oncogene.337
160960572005Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability.296
191164122009Splicing factor SFRS1 recognizes a functionally diverse landscape of RNA transcripts.143
222459672012The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation.135
184398972008The splicing factor SF2/ASF regulates translation initiation by enhancing phosphorylation of 4E-BP1.113
152109562004A molecular link between SR protein dephosphorylation and mRNA export.109
201399842010SF2/ASF autoregulation involves multiple layers of post-transcriptional and translational control.86
264310272015SRSF1-Regulated Alternative Splicing in Breast Cancer.78
192509062009Chromatin binding of SRp20 and ASF/SF2 and dissociation from mitotic chromosomes is modulated by histone H3 serine 10 phosphorylation.74
203850902010A splicing-independent function of SF2/ASF in microRNA processing.73

Citation

Ruben Pio

SRSF1 (serine/arginine-rich splicing factor 1)

Atlas Genet Cytogenet Oncol Haematol. 2011-11-01

Online version: http://atlasgeneticsoncology.org/gene/47631/srsf1