VEGF Gene Regulation

  • Marcus Fruttiger
Part of the Molecular Biology Intelligence Unit book series (MBIU)


VEGF is best known for its angiogenic properties. Not only does it promote the growth of new blood vessels during embryonic development, it is also important in the adult, where it plays a role in maintaining an adequate supply of oxygen and nutrients to most tissues. VEGF gene regulation is controlled by different signalling pathways depending on the context in which it is expressed. Best understood is the induction of VEGF expression by hypoxia in neonates and adults, which represents an adaptive response to metabolic stress. In contrast, the mechanisms that control VEGF expression during embryonic development are currently less clear.


Vascular Endothelial Growth Factor Vascular Endothelial Growth Factor mRNA Vascular Endothelial Growth Factor Gene VEGF Expression Retinal Vasculature 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Michaelson IC. Retinal circulation in man and animals. Springfield, IL: Charles C. Thomas, 1954.Google Scholar
  2. 2.
    Shweiki D, Itin A, Soffer D et al. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992; 359(6398):843–845.PubMedCrossRefGoogle Scholar
  3. 3.
    Leung DW, Cachianes G, Kuang WJ et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246(4935):1306–1309.PubMedCrossRefGoogle Scholar
  4. 4.
    Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med 1971; 285(21):1182–1186.PubMedGoogle Scholar
  5. 5.
    Ferrara N. VEGF as a therapeutic target in cancer. Oncology 2005; 69(Suppl 3):11–16.PubMedCrossRefGoogle Scholar
  6. 6.
    Carmeliet P, Ferreira V, Breier G et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996; 380(6573):435–439.PubMedCrossRefGoogle Scholar
  7. 7.
    Ferrara N, Carver-Moore K, Chen H et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996; 380(6573):439–442.PubMedCrossRefGoogle Scholar
  8. 8.
    Forsythe JA, Jiang BH, Iyer NV et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 1996; 16(9):4604–4613.PubMedGoogle Scholar
  9. 9.
    Madan A, Curtin PT. A 24-base-pair sequence 3′ to the human erythropoietin gene contains a hypoxia-responsive transcriptional enhancer. Proc Natl Acad Sci USA 1993; 90(9):3928–3932.PubMedCrossRefGoogle Scholar
  10. 10.
    Wang GL, Semenza GL. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 1993; 90(9):4304–4308.PubMedCrossRefGoogle Scholar
  11. 11.
    Wang GL, Jiang BH, Rue EA et al. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995; 92(12):5510–55l4.PubMedCrossRefGoogle Scholar
  12. 12.
    Oosthuyse B, Moons L, Storkebaum E et al. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 2001; 28(2):131–138.PubMedCrossRefGoogle Scholar
  13. 13.
    Marti HH, Risau W. Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors. Proc Natl Acad Sci USA 1998; 95(26):15809–15814.PubMedCrossRefGoogle Scholar
  14. 14.
    Levy AP. Hypoxic regulation of VEGF mRNA stability by RNA-binding proteins. Trends Cardiovasc Med 1998; 8(6):246–250.PubMedCrossRefGoogle Scholar
  15. 15.
    Hollams EM, Giles KM, Thomson AM et al. MRNA stability and the control of gene expression: Implications for human disease. Neurochem Res 2002; 27(10):957–980.PubMedCrossRefGoogle Scholar
  16. 16.
    Meinsma D, Scheper W, Holthuizen PE et al. Site-specific cleavage of IGF-II mRNAs requires sequence elements from two distinct regions of the IGF-II gene. Nucleic Acids Res 1992; 20(19):5003–5009.PubMedCrossRefGoogle Scholar
  17. 17.
    Claffey KP, Shih SC, Mullen A et al. Identification of a human VPF/VEGF 3′ untranslated region mediating hypoxia-induced mRNA stability. Mol Biol Cell 1998; 9(2):469–481.PubMedGoogle Scholar
  18. 18.
    Zhao Z, Chang FC, Furneaux HM. The identification of an endonuclease that cleaves within an HuR binding site in mRNA. Nucleic Acids Res 2000; 28(14):2695–2701.PubMedCrossRefGoogle Scholar
  19. 19.
    Nabors LB, Gillespie GY, Harkins L et al. HuR, a RNA stability factor, is expressed in malignant brain tumors and binds to adenine-and uridine-rich elements within the 3′ untranslated regions of cytokine and angiogenic factor mRNAs. Cancer Res 2001; 61(5):2154–2161.PubMedGoogle Scholar
  20. 20.
    Onesto C, Berra E, Grepin R et al. Poly(A)-binding protein-interacting protein 2, a strong regulator of vascular endothelial growth factor mRNA. J Biol Chem 2004; 279(33):34217–34226.PubMedCrossRefGoogle Scholar
  21. 21.
    Ciais D, Cherradi N, Bailly S et al. Destabilization of vascular endothelial growth factor mRNA by the zinc-finger protein TIS11b. Oncogene 2004; 23(53):8673–8680.PubMedCrossRefGoogle Scholar
  22. 22.
    Gnarra JR, Zhou S, Merrill MJ et al. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci USA 1996; 93(20):10589–10594.PubMedCrossRefGoogle Scholar
  23. 23.
    Iliopoulos O, Levy AP, Jiang C et al. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci USA 1996; 93(20):10595–10599.PubMedCrossRefGoogle Scholar
  24. 24.
    Laroia G, Sarkar B, Schneider RJ. Ubiquitin-dependent mechanism regulates rapid turnover of AU-rich cytokine mRNAs. Proc Natl Acad Sci USA 2002; 99(4):1842–1846.PubMedCrossRefGoogle Scholar
  25. 25.
    Datta K, Mondal S, Sinha S et al. Role of elongin-binding domain of von Hippel Lindau gene product on HuR-mediated VPF/VEGF mRNA stability in renal cell carcinoma. Oncogene 2005; 24(53):7850–7858.PubMedCrossRefGoogle Scholar
  26. 26.
    Shih SC, Mullen A, Abrams K et al. Role of protein kinase C isoforms in phorbol ester-induced vascular endothelial growth factor expression in human glioblastoma cells. J Biol Chem 1999; 274(22):15407–15414.PubMedCrossRefGoogle Scholar
  27. 27.
    Pages G, Berra E, Milanini J et al. Stress-activated protein kinases (JNK and p38/HOG) are essential for vascular endothelial growth factor mRNA stability. J Biol Chem 2000; 275(34):26484–26491.PubMedCrossRefGoogle Scholar
  28. 28.
    Pain VM. Initiation of protein synthesis in eukaryotic cells. Eur J Biochem 1996; 236(3):747–771.PubMedCrossRefGoogle Scholar
  29. 29.
    Kozak M. Pushing the limits of the scanning mechanism for initiation of translation. Gene 2002; 299(1–2):1–34.PubMedCrossRefGoogle Scholar
  30. 30.
    Stein I, Itin A, Einat P et al. Translation of vascular endothelial growth factor mRNA by internal ribosome entry: Implications for translation under hypoxia. Mol Cell Biol 1998; 18(6):3112–3119.PubMedGoogle Scholar
  31. 31.
    Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol 2002; 64(5–6):993–998.PubMedCrossRefGoogle Scholar
  32. 32.
    Xie K, Wei D, Shi Q et al. Constitutive and inducible expression and regulation of vascular endothelial growth factor. Cytokine Growth Factor Rev 2004; 15(5):297–324.PubMedCrossRefGoogle Scholar
  33. 33.
    Milanini J, Vinals F, Pouyssegur J et al. p42/p44 MAP kinase module plays a key role in the transcriptional regulation of the vascular endothelial growth factor gene in fibroblasts. J Biol Chem 1998; 273(29):18165–18172.PubMedCrossRefGoogle Scholar
  34. 34.
    Berra E, Milanini J, Richard DE et al. Signaling angiogenesis via p42/p44 MAP kinase and hypoxia. Biochem Pharmacol 2000; 60(8):1171–1178.PubMedCrossRefGoogle Scholar
  35. 35.
    Pages G, Pouyssegur J. Transcriptional regulation of the Vascular Endothelial Growth Factor gene—a concert of activating factors. Cardiovasc Res 2005; 65(3):564–573.PubMedCrossRefGoogle Scholar
  36. 36.
    Ryuto M, Ono M, Izumi H et al. Induction of vascular endothelial growth factor by tumor necrosis factor alpha in human glioma cells: Possible roles of SP-1. J Biol Chem 1996; 271(45):28220–28228.PubMedCrossRefGoogle Scholar
  37. 37.
    Shi Q, Le X, Abbruzzese JL et al. Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res 2001; 61(10):4143–4154.PubMedGoogle Scholar
  38. 38.
    Mukhopadhyay D, Knebelmann B, Cohen HT et al. The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Mol Cell Biol 1997; 17(9):5629–5639.PubMedGoogle Scholar
  39. 39.
    Salimath B, Marme D, Finkenzeller G. Expression of the vascular endothelial growth factor gene is inhibited by p73. Oncogene 2000; 19(31):3470–3476.PubMedCrossRefGoogle Scholar
  40. 40.
    Niu G, Wright KL, Huang M et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 2002; 21(13):2000–2008.PubMedCrossRefGoogle Scholar
  41. 41.
    Wei D, Le X, Zheng L et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 2003; 22(3):319–329.PubMedCrossRefGoogle Scholar
  42. 42.
    Michiels C, Minet E, Michel G et al. HIF-1 and AP-1 cooperate to increase gene expression in hypoxia: Role of MAP kinases. IUBMB Life 2001; 52(1–2):49–53.PubMedCrossRefGoogle Scholar
  43. 43.
    Gerald D, Berra E, Frapart YM et al. JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell 2004; 118(6):781–794.PubMedCrossRefGoogle Scholar
  44. 44.
    Gerhardt H, Golding M, Fruttiger M et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 2003; 161(6):1163–1177.PubMedCrossRefGoogle Scholar
  45. 45.
    West H, Richardson WD, Fruttiger M. Stabilization of the retinal vascular network by reciprocal feedback between blood vessels and astrocytes. Development 2005; 132(8):1855–1862.PubMedCrossRefGoogle Scholar
  46. 46.
    Vinores SA, Xiao WH, Aslam S et al. Implication of the hypoxia response element of the Vegf promoter in mouse models of retinal and choroidal neovascularization, but not retinal vascular development. J Cell Physiol 2006; 206(3):749–758.PubMedCrossRefGoogle Scholar
  47. 47.
    Chen EY, Fujinaga M, Giaccia AJ. Hypoxic microenvironment within an embryo induces apoptosis and is essential for proper morphological development. Teratology 1999; 60(4):215–225.PubMedCrossRefGoogle Scholar
  48. 48.
    Lee YM, Jeong CH, Koo SY et al. Determination of hypoxic region by hypoxia marker in developing mouse embryos in vivo: A possible signal for vessel development. Dev Dyn 2001; 220(2):175–186.PubMedCrossRefGoogle Scholar
  49. 49.
    Lawson ND, Vogel AM, Weinstein BM. Sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev Cell 2002; 3(1):127–136.PubMedCrossRefGoogle Scholar
  50. 50.
    Schwarz Q, Gu C, Fujisawa H et al. Vascular endothelial growth factor controls neuronal migration and cooperates with Sema3A to pattern distinct compartments of the facial nerve. Genes Dev 2004; 18(22):2822–2834.PubMedCrossRefGoogle Scholar
  51. 51.
    Rosenstein JM, Krum JM. New roles for VEGF in nervous tissue—beyond blood vessels. Exp Neurol 2004; 187(2):246–253.PubMedCrossRefGoogle Scholar
  52. 52.
    Storkebaum E, Lambrechts D, Carmeliet P. VEGF: Once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays 2004; 26(9):943–954.PubMedCrossRefGoogle Scholar
  53. 53.
    Loureiro RM, D’Amore PA. Transcriptional regulation of vascular endothelial growth factor in cancer. Cytokine Growth Factor Rev 2005; 16(1):77–89.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

  • Marcus Fruttiger
    • 1
  1. 1.UCL Institute of OphthalmologyUniversity College LondonLondonUK

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