Implication of the ERK Pathway on the Post-transcriptional Regulation of VEGF mRNA Stability
Vascular Endothelial Growth Factor-A (VEGF-A) is one of the most important regulators of physiological and pathological angiogenesis. Constitutive activation of the ERK pathway and over-expression of VEGF-A are common denominators of tumours of different
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Introduction Blood vessel growth and maturation are highly complex and coordinated processes involve numerous growth factors and related transduction pathways. Among them, vascular endothelial growth factor (VEGF), a potent and specific mitogen/survival factor for vascular endothelial cells, represents a crucial rate-limiting step in both physiological and pathological angiogenesis (1, 2). Its expression is induced in cancer cells as a result of hypoxia and multiple genetic alterations, including p53 and PTEN loss-offunction, RAS and SRC gain-of-function, and autocrine tyrosine kinase signalling pathways (3–8).
Rony Seger (ed.), MAP Kinase Signaling Protocols: Second Edition, Methods in Molecular Biology, vol. 661, DOI 10.1007/978-1-60761-795-2_28, © Springer Science+Business Media, LLC 2010
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Essafi-Benkhadir, Pouysségur, and Pagès
Several studies have provided evidence that the ERK1/2 pathway is actively involved in angiogenesis mediated by VEGF (9–11). The link between signalling pathways and VEGF production was established following a study examining VEGF mRNA expression in cells transformed with the constitutively active form of ERK1/2 (9). Moreover, the conditional expression of MAP Kinase phosphatase 3/Dual Specificity phosphatase 6 (MKP-3/ DUSP-6) in Ras-transformed cells blocks VEGF production and prevents the development of vascularised tumours in nude mice (12). Pathological situations are characterised by an increase in VEGF mRNA and protein levels, for example (a) Chronic myeloid leukaemia (CML) can be characterised by a chromosomal translocation between the Bcr and Abl genes which involves an increase in ERK1/2 activity (13). The inhibition of this signalling pathway by imatinib mesylate (Gleevec) standardises the rate of VEGF production in cellular models of CML and among patients in cytogenetic remission (14). (b) Helicobacter pylori infection involves an increase in ERK1/2 activity, VEGF mRNA and protein levels (15). The increased VEGF expression is related to an increase in gene transcription, mRNA stability and translation. A combination of these phenomena is also possible. The link between ERK1/2 signalling and VEGF transcription has been partially determined. Milanini et al. demonstrated that ERK1/2 up-regulate the transcription of the VEGF gene, an action mediated via the ERK1/2-dependent phosphorylation of Sp1 and Sp3 transcription factors. Phosphorylation sites have been identified (16, 17). The Sp transcription factors were also described as markers of tumour aggressiveness. This characteristic is probably related to their capacity to induce excessive angiogenesis throughout tumour development (18–20). Transcription of the VEGF gene is also increased following hypoxia via Hypoxia Inducible Factor (HIF-1). However, both growth factors and hypoxia induce the expression of HIF-1. This phenomenon is partly due to direct phosphorylation of HIF-1a by ERK1/2 allowing its accumulation in the nucleus (21) and an increase in its transactivation activity (22). A number of genes are post-tra
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