Regulation of Vegfa Expression

Several mechanisms regulate VEGF-A expression, including oxygen concentration, low pH, oncogenes and tumor suppressor genes, cytokines, hormones, and a variety of other mediators.

Oxygen Concentration and Low pH

Hypoxia potently upregulates VEGF-A expression, both by stabilizing its message and by increasing message transcription. Transcriptional regulation is mediated through hypoxia-inducible factor 1 (HIF-1), a heterodimeric protein transcription factor. One HIF-1 component, HIF-1a, is rapidly degraded under normoxic conditions by the ubiquitin pathway; however, when stabilized by hypoxia, HIF-1 a dimerizes with HIF-1 b, and the complex binds to and activates a hypoxia-responsive element in the VEGF-A promoter. Hypoxic regulation of VEGF-A expression is likely important in healing wounds and has been demonstrated in some tumors. However, many tumors express VEGF-A con-stitutively at high levels even under normoxic conditions, and therefore, regulation is achieved by other means, such as those discussed as follows.

Low pH, another hallmark of tumors and ischemic tissues, also upregulates VEGF and does so independently of HIF-1.

Oncogenes and Tumor Suppressor Genes

Several oncogenes (src, ras) and tumor suppressor genes (p53, p73, von Hippel Lindau [vHL]) modulate VEGF-A expression and in this way can modulate tumor growth. Cells transfected with mutant src or ras oncogenes express increased amounts of VEGF-A mRNA and protein. The vHL tumor suppressor gene is part of the protein complex that targets specific proteins, including HIF-1a, for ubiquitinyla-tion and proteolysis. Therefore, when vHL is absent or inactivated, HIF-1 a is stabilized even under normoxic conditions with resulting upregulation of VEGF-A and perhaps other members of the VPF/VEGF family. The p53 and p73 genes suppress VEGF-A transcription.

Cytokines and Other Mediators

Numerous growth factors, cytokines, and lipid mediators upregulate VEGF-A expression in different cells, including EGF, TGF-a, FGF-2, TGF-b, PDGF, keratinocyte growth factor, TNF, interleukins 1 and 6, insulin-like growth factor 1, HGF, and prostaglandins E1 and E2. These findings are likely to be important in autocrine regulation of VEGF-A

expression in vivo in that many tumors that express VEGF-A also express other cytokines and their receptors (e.g., TGF-a, FGF-2, EGF).

Hormones

VEGF-A is expressed by many cells that make steroid hormones (adrenal cortex, corpus luteum, Leydig cells) and by cells that are under hormonal regulation (e.g., the cycling uterus and ovary). Circulating VEGF-A levels and presumably VEGF-A expression correlate with estrogen receptor positivity in breast cancer. VEGF-A is also expressed by peptide hormone-producing cells such as thyroid follicular cells, and its production in culture is upregulated by agents such as insulin, dibutyryl c-AMP, and the IgG of Graves' disease. Thyroid-stimulating hormone upregulates VEGF-A mRNA expression in human thyroid follicles and promotes VEGF-A secretion in several thyroid cancer cell lines.

Other Agents

Several other chemicals, proteins, and processes can augment VEGF-A expression or activity by direct or indirect means, including thrombin, platelet aggregation, shear stress, acidosis, lysophosphatidic acid, and adenosine. On the other hand, dexamethasone downregulates or prevents cytokine- (but not hypoxia-) induced upregulation of VEGF-A expression.

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