Vascular endothelial growth factor (VEGF) promotes angiogenesis. VEGF has different isoforms with different functions that are generated by alternative splicing (AS).There are several proteins that participate in splicing, including serine-arginine-rich splicing factors (SRSF).SRSF are activated by kinases such as serine arginine rich protein kinases (SRPKs). Hypoxia has been shown to upregulate VEGF in several cancers. Others have demonstrated that hypoxia up-regulates SRSF proteins, which subsequently increases just the VEGF 121 isoforms in endometrial carcinoma cells. We previously showed that in hypoxic leukemia cells VEGF isoforms were spliced differently and VEGF 121 levels were inversely correlated with levels of WT1, a transcription factor. In acute lymphoblastic leukemia cells, VEGF165 and WT1 were significantly increased by hypoxia. In chronic myelogenous leukemia cells, hypoxia increased both VEGF165 and VEGF121 levels with little change in WT1 levels. Since others have shown that WT1 suppresses SRPK1 levels in sarcoma cells, our data in leukemia cells were consistent with an inverse relation between WT1 and VEGF 121 levels. The aim of this study was to determine if hypoxic conditions activated SRPK1/SRPK2 in leukemic cells to alter splicing of VEGF isoforms. The results indicated that hypoxia does not change mRNA levels of SRPK1/SRPK2, although protein levels need to be examined. Another possible explanation could be that other splicing kinases may be responsible for altering the VEGF 121 levels in leukemia cells. A better understanding of the mechanism of AS of VEGF could lead to new therapy targeting specific isoforms.
Dr. Gail Fraizer
Serine-arginine-rich (SR) splicing factors are found in the spliceosome that carries out the splicing of exons. Kinases including serine arginine rich protein kinases (SRPKs) activate SR splicing factors. SRPK1 functions in splicing vascular endothelial growth factor (VEGF). The aim of this study was to determine if hypoxic conditions could activate SRPK1/SRPK2 in leukemia cells that splice VEGF isoforms. The results have indicated that hypoxia does not change SRPK1/SRPK2 mRNA levels but protein levels need to be examined. Another possible explanation is that other splicing kinases may be responsible for altering the VEGF 121 levels in leukemia cells. A better understanding of the mechanism of splicing of VEGF could lead to new therapy targeting specific isoforms.