Alternative Splicing: A Promising Target for Pharmaceutical Inhibition of Pathological Angiogenesis?

Carine      Munaut; Alain      C. Colige; Charles      A. Lambert

doi:10.2174/138161210794455012

Abstract

In eukaryotes, genes consist in coding sequences (exons) interspersed with non-coding ones (introns). The regulation of alternative inclusion/exclusion of exons, or part of exons, during the maturation of the pre-mRNA into mRNA (alternative splicing) allows a dramatic increase of the protein versus the gene repertoire. In a number of cases, alternative splicing decision generates proteins with distinct, sometimes opposite, functions from a given gene. Angiogenesis is the process of vascularisation in physiological conditions and a series of pathologies, including cancer where it favours tumour progression and dissemination of metastasis. In this issue, we discuss some key examples showing how alternative splicing may induce a switch from anti-angiogenic to pro-angiogenic functions reciprocally. For some of these splicing events, the molecular mechanisms that trigger alternative splicing toward one or the other direction start to be elucidated. The emergence of strategies enabling to regulate alternative splicing opens new routes for anti-angiogenic therapies.

Keywords: Alternative splicing, angiogenesis, small molecules angiogenesis inhibitors, VEGF, VEGF111, constitutive splicing, isoforms, SRPK, ischemia, hypertension, preeclampsia, Denys-Drash syndrome, ELISA, Neuropilins, RTKs, metalloproteinase-17, semaphorins, plexin-1, Sema3A, Tie-2, Ang-2, VASH1, SULF-1, CAM assay, SDF-1, CXCR4, CXCR7, Neuregulin-2, Fibronectin, Migration-stimulating factor, MSF, CD44, PECAM-1/CD31, MAPK/ERK, HYAL-1, Hyaluronidase-1, TrpRS, Signalling Molecules, KLF6, camptothecin, doxorubicin, cis-platinum, Epigallocatechin gallate, Duch-ene muscular dystrophy, HDAC, Topoisomerase I, Topoisomerase II, CLK kinases, GSK3, Protein phosphatase 1, cAMP pathway, Transcription-splicing coupling, cystic fibrosis