Download Gene Section SRSF1 (serine/arginine rich splicing factor 1) -

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
SRSF1 (serine/arginine-rich splicing factor 1)
Ruben Pio
Department of Biochemistry and Division of Oncology (CIMA), University of Navarra, Pamplona, Spain
(RP)
Published in Atlas Database: November 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/SRSF1ID47631ch17q22.html
DOI: 10.4267/2042/47303
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: ASF, FLJ53078, MGC5228, SF2,
SF2p33, SFRS1, SRp30a
HGNC (Hugo): SRSF1
Location: 17q22
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.
DNA/RNA
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.
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.
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.
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.
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.
Pseudogene
No known pseudogenes.
Protein
Description
248 amino acids, 28 kDa.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(4)
286
SRSF1 (serine/arginine-rich splicing factor 1)
Pio R
SF2/ASF is also involved in transcription, mRNA
export, nonsense-mediated mRNA decay, and
translation.
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.
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.
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.
Mutations
Cell motility
Note
No mutations have been reported. Gene amplification
has been found in some tumor types.
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.
Implicated in
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.
References
Ge H, Manley JL. A protein factor, ASF, controls cell-specific
alternative splicing of SV40 early pre-mRNA in vitro. Cell. 1990
Jul 13;62(1):25-34
Krainer AR, Conway GC, Kozak D. Purification and
characterization of pre-mRNA splicing factor SF2 from HeLa
cells. Genes Dev. 1990a Jul;4(7):1158-71
Krainer AR, Conway GC, Kozak D. The essential pre-mRNA
splicing factor SF2 influences 5' splice site selection by
activating proximal sites. Cell. 1990b Jul 13;62(1):35-42
Ge H, Zuo P, Manley JL. Primary structure of the human
splicing factor ASF reveals similarities with Drosophila
regulators. Cell. 1991 Jul 26;66(2):373-82
Non-small cell lung cancer (NSCLC)
Note
SF2/ASF and survivin expression are involved in nonsmall 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.
Mayeda A, Krainer AR. Regulation of alternative pre-mRNA
splicing by hnRNP A1 and splicing factor SF2. Cell. 1992 Jan
24;68(2):365-75
Zahler AM, Lane WS, Stolk JA, Roth MB. SR proteins: a
conserved family of pre-mRNA splicing factors. Genes Dev.
1992 May;6(5):837-47
Zuo P, Manley JL. The human splicing factor ASF/SF2 can
specifically recognize pre-mRNA 5' splice sites. Proc Natl Acad
Sci U S A. 1994 Apr 12;91(8):3363-7
Prostate cancer
Misteli T, Cáceres JF, Spector DL. The dynamics of a premRNA splicing factor in living cells. Nature. 1997 May
29;387(6632):523-7
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.
Cáceres JF, Screaton GR, Krainer AR. A specific subset of SR
proteins shuttles continuously between the nucleus and the
cytoplasm. Genes Dev. 1998 Jan 1;12(1):55-66
Hanamura A, Cáceres JF, Mayeda A, Franza BR Jr, Krainer
AR. Regulated tissue-specific expression of antagonistic premRNA splicing factors. RNA. 1998 Apr;4(4):430-44
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.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(4)
McNally LM, McNally MT. An RNA splicing enhancer-like
sequence is a component of a splicing inhibitor element from
Rous sarcoma virus. Mol Cell Biol. 1998 Jun;18(6):3103-11
Kruhlak MJ, Lever MA, Fischle W, Verdin E, Bazett-Jones DP,
Hendzel MJ. Reduced mobility of the alternate splicing factor
287
SRSF1 (serine/arginine-rich splicing factor 1)
Pio R
(ASF) through the nucleoplasm and steady state speckle
compartments. J Cell Biol. 2000 Jul 10;150(1):41-51
Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D, Krainer
AR. The gene encoding the splicing factor SF2/ASF is a protooncogene. Nat Struct Mol Biol. 2007 Mar;14(3):185-93
Pagani F, Buratti E, Stuani C, Romano M, Zuccato E, Niksic M,
Giglio L, Faraguna D, Baralle FE. Splicing factors induce cystic
fibrosis transmembrane regulator exon 9 skipping through a
nonevolutionary conserved intronic element. J Biol Chem.
2000 Jul 14;275(28):21041-7
Karni R, Hippo Y, Lowe SW, Krainer AR. The splicing-factor
oncoprotein SF2/ASF activates mTORC1. Proc Natl Acad Sci
U S A. 2008 Oct 7;105(40):15323-7
Fay J, Kelehan P, Lambkin H, Schwartz S. Increased
expression of cellular RNA-binding proteins in HPV-induced
neoplasia and cervical cancer. J Med Virol. 2009
May;81(5):897-907
Aubol BE, Chakrabarti S, Ngo J, Shaffer J, Nolen B, Fu XD,
Ghosh G, Adams JA. Processive phosphorylation of alternative
splicing factor/splicing factor 2. Proc Natl Acad Sci U S A. 2003
Oct 28;100(22):12601-6
Long JC, Caceres JF. The SR protein family of splicing factors:
master regulators of gene expression. Biochem J. 2009 Jan
1;417(1):15-27
Fischer DC, Noack K, Runnebaum IB, Watermann DO,
Kieback DG, Stamm S, Stickeler E. Expression of splicing
factors in human ovarian cancer. Oncol Rep. 2004
May;11(5):1085-90
Ezponda T, Pajares MJ, Agorreta J, Echeveste JI, LópezPicazo JM, Torre W, Pio R, Montuenga LM. The oncoprotein
SF2/ASF promotes non-small cell lung cancer survival by
enhancing survivin expression. Clin Cancer Res. 2010 Aug
15;16(16):4113-25
Ghigna C, Giordano S, Shen H, Benvenuto F, Castiglioni F,
Comoglio PM, Green MR, Riva S, Biamonti G. Cell motility is
controlled by SF2/ASF through alternative splicing of the Ron
protooncogene. Mol Cell. 2005 Dec 22;20(6):881-90
Olshavsky NA, Comstock CE, Schiewer MJ, Augello MA,
Hyslop T, Sette C, Zhang J, Parysek LM, Knudsen KE.
Identification of ASF/SF2 as a critical, allele-specific effector of
the cyclin D1b oncogene. Cancer Res. 2010 May
15;70(10):3975-84
Jacquenet S, Decimo D, Muriaux D, Darlix JL. Dual effect of
the SR proteins ASF/SF2, SC35 and 9G8 on HIV-1 RNA
splicing and virion production. Retrovirology. 2005 May 22;2:33
Xu X, Yang D, Ding JH, Wang W, Chu PH, Dalton ND, Wang
HY, Bermingham JR Jr, Ye Z, Liu F, Rosenfeld MG, Manley
JL, Ross J Jr, Chen J, Xiao RP, Cheng H, Fu XD. ASF/SF2regulated CaMKIIdelta alternative splicing temporally
reprograms excitation-contraction coupling in cardiac muscle.
Cell. 2005 Jan 14;120(1):59-72
Somberg M, Schwartz S. 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 HPV16 genome. J Virol. 2010 Aug;84(16):8219-30
This article should be referenced as such:
Buratti E, Stuani C, De Prato G, Baralle FE. SR proteinmediated inhibition of CFTR exon 9 inclusion: molecular
characterization of the intronic splicing silencer. Nucleic Acids
Res. 2007;35(13):4359-68
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(4)
Pio R. SRSF1 (serine/arginine-rich splicing factor 1). Atlas
Genet Cytogenet Oncol Haematol. 2012; 16(4):286-288.
288