SRSF1 (serine/arginine-rich splicing factor 1)

2011-11-01 Ruben Pio Affiliation

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

Identity

HGNC

SRSF1

LOCATION

17q22

LOCUSID

6426

ALIAS

ASF,SF2,SF2p33,SFRS1,SRp30a

FUSION GENES

Show Gene Fusions

DNA/RNA

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

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.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
14555757	2003	Processive phosphorylation of alternative splicing factor/splicing factor 2.	Aubol BE et al
17576688	2007	SR protein-mediated inhibition of CFTR exon 9 inclusion: molecular characterization of the intronic splicing silencer.	Buratti E et al
9420331	1998	A specific subset of SR proteins shuttles continuously between the nucleus and the cytoplasm.	Cáceres JF et al
20682707	2010	The oncoprotein SF2/ASF promotes non-small cell lung cancer survival by enhancing survivin expression.	Ezponda T et al
19319956	2009	Increased expression of cellular RNA-binding proteins in HPV-induced neoplasia and cervical cancer.	Fay J et al
15069551	2004	Expression of splicing factors in human ovarian cancer.	Fischer DC et al
2163768	1990	A protein factor, ASF, controls cell-specific alternative splicing of SV40 early pre-mRNA in vitro.	Ge H et al
1855257	1991	Primary structure of the human splicing factor ASF reveals similarities with Drosophila regulators.	Ge H et al
16364913	2005	Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene.	Ghigna C et al
9630249	1998	Regulated tissue-specific expression of antagonistic pre-mRNA splicing factors.	Hanamura A et al
15907217	2005	Dual effect of the SR proteins ASF/SF2, SC35 and 9G8 on HIV-1 RNA splicing and virion production.	Jacquenet S et al
18832178	2008	The splicing-factor oncoprotein SF2/ASF activates mTORC1.	Karni R et al
17310252	2007	The gene encoding the splicing factor SF2/ASF is a proto-oncogene.	Karni R et al
2364434	1990	The essential pre-mRNA splicing factor SF2 influences 5' splice site selection by activating proximal sites.	Krainer AR et al
10893255	2000	Reduced mobility of the alternate splicing factor (ASF) through the nucleoplasm and steady state speckle compartments.	Kruhlak MJ et al
19061484	2009	The SR protein family of splicing factors: master regulators of gene expression.	Long JC et al
1531115	1992	Regulation of alternative pre-mRNA splicing by hnRNP A1 and splicing factor SF2.	Mayeda A et al
9584151	1998	An RNA splicing enhancer-like sequence is a component of a splicing inhibitor element from Rous sarcoma virus.	McNally LM et al
9168118	1997	The dynamics of a pre-mRNA splicing factor in living cells.	Misteli T et al
20460515	2010	Identification of ASF/SF2 as a critical, allele-specific effector of the cyclin D1b oncogene.	Olshavsky NA et al
10766763	2000	Splicing factors induce cystic fibrosis transmembrane regulator exon 9 skipping through a nonevolutionary conserved intronic element.	Pagani F et al
20519389	2010	Multiple 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
15652482	2005	ASF/SF2-regulated CaMKIIdelta alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle.	Xu X et al
1577277	1992	SR proteins: a conserved family of pre-mRNA splicing factors.	Zahler AM et al
7512732	1994	The 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 ID	Transcript ID	Uniprot
ENSG00000136450	ENST00000258962	Q07955
ENSG00000136450	ENST00000581979	Q07955
ENSG00000136450	ENST00000582730	Q07955
ENSG00000136450	ENST00000583741	J3QQV5
ENSG00000136450	ENST00000584668	J3KSR8
ENSG00000136450	ENST00000584773	J3KTL2
ENSG00000136450	ENST00000585096	J3KSW7

Expression (GTEx)

100

150

200

250

300

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Spliceosome	KEGG	ko03040
Spliceosome	KEGG	hsa03040
Herpes simplex infection	KEGG	ko05168
Herpes simplex infection	KEGG	hsa05168
Gene Expression	REACTOME	R-HSA-74160
RNA Polymerase II Transcription	REACTOME	R-HSA-73857
RNA Polymerase II Transcription Termination	REACTOME	R-HSA-73856
Cleavage of Growing Transcript in the Termination Region	REACTOME	R-HSA-109688
Processing of Capped Intron-Containing Pre-mRNA	REACTOME	R-HSA-72203
mRNA Splicing	REACTOME	R-HSA-72172
mRNA Splicing - Major Pathway	REACTOME	R-HSA-72163
mRNA Splicing - Minor Pathway	REACTOME	R-HSA-72165
mRNA 3'-end processing	REACTOME	R-HSA-72187
Transport of Mature Transcript to Cytoplasm	REACTOME	R-HSA-72202
Transport of Mature mRNA derived from an Intron-Containing Transcript	REACTOME	R-HSA-159236
IL-17 signaling pathway	KEGG	ko04657
IL-17 signaling pathway	KEGG	hsa04657

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
38294104	2024	TIM22 and TIM29 inhibit HBV replication by up-regulating SRSF1 expression.	1
38369277	2024	RNA Binding Proteins that Mediate LPS-induced Alternative Splicing of the MyD88 Innate Immune Regulator.	0
38567732	2024	Unearthing a novel function of SRSF1 in binding and unfolding of RNA G-quadruplexes.	0
38581057	2024	Circ_0001786 facilitates gefitinib resistance and malignant progression in non-small cell lung cancer via miR-34b-5p/SRSF1.	1
38735973	2024	High expression of SRSF1 facilitates osteosarcoma progression and unveils its potential mechanisms.	0
38743621	2024	SRSF1 interactome determined by proximity labeling reveals direct interaction with spliceosomal RNA helicase DDX23.	1
39023093	2024	The U1-70K and SRSF1 interaction is modulated by phosphorylation during the early stages of spliceosome assembly.	1
38294104	2024	TIM22 and TIM29 inhibit HBV replication by up-regulating SRSF1 expression.	1
38369277	2024	RNA Binding Proteins that Mediate LPS-induced Alternative Splicing of the MyD88 Innate Immune Regulator.	0
38567732	2024	Unearthing a novel function of SRSF1 in binding and unfolding of RNA G-quadruplexes.	0
38581057	2024	Circ_0001786 facilitates gefitinib resistance and malignant progression in non-small cell lung cancer via miR-34b-5p/SRSF1.	1
38735973	2024	High expression of SRSF1 facilitates osteosarcoma progression and unveils its potential mechanisms.	0
38743621	2024	SRSF1 interactome determined by proximity labeling reveals direct interaction with spliceosomal RNA helicase DDX23.	1
39023093	2024	The U1-70K and SRSF1 interaction is modulated by phosphorylation during the early stages of spliceosome assembly.	1
36508830	2023	CircCDR1as mediates PM(2.5)-induced lung cancer progression by binding to SRSF1.	2

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