GTMB 7 - Gene Therapy & Molecular Biology

Gene Therapy and Molecular Biology Vol 7, page 69Gene Ther Mol Biol Vol 7, 69-73, 2003Regulation of vascular endothelial growth factor byhypoxiaMini ReviewIlana Goldberg-Cohen*, Nina S Levy, Andrew P LevyTechnion Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel__________________________________________________________________________________*Correspondence: Ilana Goldberg-Cohen, Technion Faculty of Medicine, Haifa, Israel; Tel 011-972-4-8295202; Fax 011-972-4-8514103; email: gilana@tx.technion.ac.ilKey words: VEGF (vascular endothelial growth factor), hypoxia, HuRReceived: 04 June 2003; Accepted: 27 June 2003; electronically published: July 2003SummaryThe past few decades have singled out the growth of new blood vessels, termed angiogenesis, as a key process in thecourse of normal development as well as in pathological disease processes. VEGF, an endothelial cell specificmitogen, is now accepted as a key mediator of angiogenic events and as such may be a powerful tool in manipulatingthe growth of new blood vessels. VEGF expression is regulated to a great extent by hypoxia. The lack of oxygen tosupply a tissue triggers several molecular mechanisms that increase VEGF mRNA transcription, stability andtranslation, and thus upregulate the expression of VEGF protein. This review focuses on the increase in VEGFmRNA stability through its recognition by the RNA binding protein HuR. Binding of HuR to its cognate site on the3´UTR of VEGF mRNA results in a several fold increase in VEGF mRNA stability, possibly due to the masking of anearby binding site for ribonucleases. Mastering the regulatory mechanisms of VEGF expression is of greatimportance for the future manipulation of VEGF and angiogenesis in the disease setting.I. IntroductionThe ability to grow new blood vessels to supply theneeds of a growing tissue is critical in both physiologicalprocesses such as embryogenesis and in pathologicalprocesses that include tumor growth and metastasis.Vascular Endothelial Growth Factor (VEGF), anendothelial cell specific mitogen, (Ferrara and Henzel,1989; Plouet et al, 1989) is a critical mediator in theestablishment of new blood vessels in bothvasculogenesis, the de novo foundation of vascularsystems (Risau, 1997), and angiogenesis, the developmentof new blood vessels from a pre existing network (Risau,1997). The VEGF gene, found on chromosome 6p21(Vincenti et al, 1996), consists of eight exons separated byseven introns and is alternatively spliced to form fivedifferent VEGF isoforms, the most prominent beingVEGF 165 , that differ in length and ability to bind heparin(Houck et al, 1991).Two tyrosine kinase family receptors flt-1(VEFGR1) and flk-1 (VEGFR2) were identified as VEGFreceptors (de Vries et al, 1992; Terman et al, 1992). Theyhave a similar structure of seven immunoglobulin-likeloops in their extracellular domain, a transmembraneregion and a tyrosine kinase consensus sequence (Shibuyaet al, 1990; Terman et al, 1991). The two receptors inducedifferent signal transduction cascades when activated andthus mediate separate responses to VEGF (Waltenberger etal, 1994; Yoshida et al, 1996). A third receptor familyunrelated to the receptor families described above, theneuropillin receptor family, binds mainly to VEGF 165 andits members are thought to act as coreceptors (Soker et al,1996).II. Regulation of VEGF geneexpressionIn light of its potency and importance in vasculaturedevelopment, VEGF itself is carefully regulated to providefor the appropriate amount of VEGF at the appropriatetime. Growth factors, cytokines and other extracellularmolecules such as PDGF, TNFα and others influenceangiogenesis by governing VEGF expression (Deroanne etal, 1997; Finkenzeller et al, 1997; Frank et al, 1995;Pertovaara et al, 1994; Ryuto et al, 1996). Oncogenes andtumor suppressor genes also play a role in VEGFmodulation as in the case of the von Hipple Lindau tumorsuppressor gene whose absence or inactivationdramatically increases VEGF expression (Iliopoulos et al,1996; Maher and Kaelin, 1997; Mukhopadhyay et al,1997).69