VEGF Splicing and the Role of VEGF Splice Variants: From Physiological-Pathological Conditions to Specific Pre-mRNA Splicing.
During this past decade, the vascular endothelial growth factor (VEGF) pathway has been extensively studied. VEGF is a paradigm of molecular regulation since its expression is controlled at all possible steps including transcription, mRNA stability, translation, and pre-mRNA splicing. The latter form of molecular regulation is probably the least studied. This field has been neglected; yet different forms of VEGF with different sizes and different physiological properties issued from alternative splicing have been described a long time ago. Recently a new level of complexity was added to the field of splicing of VEGF pre-mRNA. Whereas thousands of publications have described VEGF as a pro-angiogenic factor, an alternative splicing event generates specific anti-angiogenic forms of VEGF that only differ from the others by a modification in the last six amino acids of the protein. According to the scientists who discovered these isoforms, which are indistinguishable from the pro-angiogenic ones with pan VEGF antibodies, some of the literature on VEGF is at least inexact if not completely false. Moreover, the presence of anti-angiogenic forms of VEGF may explain the disappointing efficacy of anti-VEGF therapies on the overall survival of patients with different forms of cancers and with wet age-related macular degeneration. This review focuses on the existence of the different alternative splice variants of VEGF and the molecular mechanisms associated with their expression and function.
Institute for Research on Cancer and Aging of Nice (IRCAN), University of Nice Sophia Antipolis, Centre Antoine Lacassagne 33 Avenue de Valombrose, UMR CNRS 7284/INSERM U 1081, Nice, 06189, France.
Mélanie
M
Guyot
Gilles
G
Pagès
D017398:Alternative Splicing; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics; D020033:Protein Isoforms; D021381:Protein Transport; D012322:RNA Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D020033:Protein Isoforms; D012322:RNA Precursors; D012333:RNA, Messenger; D042442:Vascular Endothelial Growth Factors