9th March - Splicing in Cancer Flashcards
What mutation in splicing causes retinitis pigmentosa?
Prp8
What are the causes of myelodysplasia as found by Yoshkas sequencing on white blood cells in 2011?
Mutation hotspots in U2F65, SF3B1, U2AF35, SF1
Some exons have different splice site signals detected by U11 and not U1
What is myelodysplasia?
Disease which leads to leukaemia, cells loose control of proliferation but are not fully dysregulated yet
What mutation occurs in 4% of bladder urothelial carcinoma?
SF3B1
What cancers is SRSF1 OE common in?
Lung
Breast
Ovary
How does c-Myc amplification cause splicing errors?
Increases global expression so splicing apparatus can’t cope –> unsplice RNA
Co-operates with SRSF1
Why is SRSF1 OE in breast cancer?
It binds ESEs containing GGA motifs and recruits spliceosomal functions
It promotes anti-apoptotic isoforms of BIN1, BIM and CASC4
It promotes splicing of proliferative isofomrs of MKNK2, S6K1 and CASC4
Why is splicing important in apoptosis?
Many apoptotic genes also express anti-apoptotic isoforms
E.G. BCL-XL (Anti-apoptotic), BCL XS (Pro-apoptotic)
E.G. Caspase 9 (Active), Caspase 9b (Inactive)
Describe the alternative splicing of BCL-XL
It has two alternative 5’ss
The downstream ss creates BCL-XL (Anti-apoptotic form)
The upstream ss creastes BCL-XS (Pro-apoptotic form)
What is the role of SRSF1 in the EMT?
SRSF1 promotes EMT
SRSF1 has a massive 3’UTR which contains an optional intron, if this intron is spliced it makes SRSF1 unstable and therefore it is degraded. SRSF1 suppresses RON splicing of exon 11 (lead to isoform which can’t enter the plasma membrane therefore is constitutively active)
How does SRSF1 influence tumour angiogenesis?
2nd isoform of VEGF will prevent blood supply to tumour
The choice of isoform is decided by SRSF1, which promotes the 1st isoform of VEGF thus promotes angiogenesis
