Gene Therapy and Molecular Biology Vol 7, page 69 Gene Ther Mol Biol Vol 7, 69-73, 2003
Regulation of vascular endothelial growth factor by hypoxia Mini Review
Ilana Goldberg-Cohen*, Nina S Levy, Andrew P Levy Technion 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 011-972-48514103; email: gilana@tx.technion.ac.il Key words: VEGF (vascular endothelial growth factor), hypoxia, HuR Received: 04 June 2003; Accepted: 27 June 2003; electronically published: July 2003
Summary The past few decades have singled out the growth of new blood vessels, termed angiogenesis, as a key process in the course of normal development as well as in pathological disease processes. VEGF, an endothelial cell specific mitogen, is now accepted as a key mediator of angiogenic events and as such may be a powerful tool in manipulating the growth of new blood vessels. VEGF expression is regulated to a great extent by hypoxia. The lack of oxygen to supply a tissue triggers several molecular mechanisms that increase VEGF mRNA transcription, stability and translation, and thus upregulate the expression of VEGF protein. This review focuses on the increase in VEGF mRNA stability through its recognition by the RNA binding protein HuR. Binding of HuR to its cognate site on the 3´UTR of VEGF mRNA results in a several fold increase in VEGF mRNA stability, possibly due to the masking of a nearby binding site for ribonucleases. Mastering the regulatory mechanisms of VEGF expression is of great importance for the future manipulation of VEGF and angiogenesis in the disease setting. different signal transduction cascades when activated and thus mediate separate responses to VEGF (Waltenberger et al, 1994; Yoshida et al, 1996). A third receptor family unrelated to the receptor families described above, the neuropillin receptor family, binds mainly to VEGF165 and its members are thought to act as coreceptors (Soker et al, 1996).
I. Introduction The ability to grow new blood vessels to supply the needs of a growing tissue is critical in both physiological processes such as embryogenesis and in pathological processes that include tumor growth and metastasis. Vascular Endothelial Growth Factor (VEGF), an endothelial cell specific mitogen, (Ferrara and Henzel, 1989; Plouet et al, 1989) is a critical mediator in the establishment of new blood vessels in both vasculogenesis, the de novo foundation of vascular systems (Risau, 1997), and angiogenesis, the development of 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 by seven introns and is alternatively spliced to form five different VEGF isoforms, the most prominent being VEGF165, 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 VEGF receptors (de Vries et al, 1992; Terman et al, 1992). They have a similar structure of seven immunoglobulin-like loops in their extracellular domain, a transmembrane region and a tyrosine kinase consensus sequence (Shibuya et al, 1990; Terman et al, 1991). The two receptors induce
II. Regulation expression
of
VEGF
gene
In light of its potency and importance in vasculature development, VEGF itself is carefully regulated to provide for the appropriate amount of VEGF at the appropriate time. Growth factors, cytokines and other extracellular molecules such as PDGF, TNF! and others influence angiogenesis by governing VEGF expression (Deroanne et al, 1997; Finkenzeller et al, 1997; Frank et al, 1995; Pertovaara et al, 1994; Ryuto et al, 1996). Oncogenes and tumor suppressor genes also play a role in VEGF modulation as in the case of the von Hipple Lindau tumor suppressor gene whose absence or inactivation dramatically increases VEGF expression (Iliopoulos et al, 1996; Maher and Kaelin, 1997; Mukhopadhyay et al, 1997).
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