The People of Tulane Cancer Center Research
Aline Betancourt, PhD
Dr. Betancourt's research focuses on oxygen-sensing genetic mechanisms, post-transcriptional control of oxygen-regulated genes, RNA binding proteins, angiogenesis and cancer research. Tumors require the formation of new blood vessels, angiogenesis, to grow. Targeting angiogenesis provides a novel approach for cancer therapy that rivals conventional therapy since drug resistance and tissue toxicity issues are avoided. Tumor angiogenesis depends on a balance between tumor-dependent angiogenic factors like VEGF (vascular endothelial growth factor) and host anti-angiogenic peptides like endostatin and angiostatin. The ability to alter this balance by favoring the anti-angiogenic effect by treatment with exogenous endostatin and angiostatin has been demonstrated. However, a major difficulty in translating these strategies to the clinic is the lack of large quantities of these peptides for long-term treatment. An alternative strategy to disturb this balance is to disrupt VEGF or other angiogenic factor production. EGF, like the hematopoietic growth factor erythropoietin (Epo), is usually synthesized following low oxygen or hypoxic stress. Since VEGF is a potent mitogen for vascular endothelial cells this response represents a means to quickly develop new blood vessels to bring oxygenated red blood cells and rescue the stressed tissue. Growing tumor cells become hypoxic and trigger or exploit this normal physiologic process. VEGF and Epo induction by hypoxia is largely controlled at the level of message stability. Post-transcriptional mechanisms have been implicated for VEGF and Epo since a physiologic drop in oxygen tension leads to induction of gene expression. However, increases in mRNA transcription does not exactly parallel the observed increased level of expression; thus it has been postulated that post-transcriptional stabilization of the normally labile VEGF and Epo mRNAs may account for the observed increased VEGF and Epo levels. Investigations in this laboratory have identified a complex of proteins, erythropoietin mRNA binding protein complex (ERBP30 and 70), in cytoplasmic lysates of human hepatocellular carcinoma (Hep3B) cells which specifically bind to a 120 nucleotide (nt) region in the 3' untranslated region (UTR) of Epo mRNA, VEGF mRNA as well as tyrosine hydroxylase (TH) mRNA. Additionally, a stabilizing role has been suggested for this region from studies in which deletion of this 120 nt region lead to an unchanged mRNA half-life in response to hypoxia (6 hrs) as compared to a forty percent increase in half-life observed for the wild-type mRNA. Production of VEGF and Epo is likely to be controlled post-transcriptionally by specific binding of the ERBP30 and ERBP70 complex to the 3' UTR of the VEGF and Epo mRNA. Current efforts are centered on understanding oxygen-sensing at the post-transcriptional level with the hypothesis that ERBP30 and ERBP70 are common post-transcriptional factors involved in oxygen-sensing.
Scandurro AB, Rondon IJ, Wilson RB, Tennenbaum SA, Garry RF, Beckman BS. (1997) Interaction of erythropoietin RNA binding protein with mRNA requires an association with heat shock protein 70. Kidney Int 51(2): 579-584.
Mallia CM, Aguirre V, McGary E, Tang Y, Scandurro AB, Liu C, Noguchi CT, Beckman BS. (1998) Protein kinase C is an effector of hexamethylene bisacetamide-induced differentiation of friend erythroleukemia cells. Exp Cell Res 246: 348-354.
Scandurro AB, Beckman BS. (1998) Common Proteins bind mRNAs encoding Erythropoietin, Tyrosine Hydroxylase and Vascular Endothelial Growth Factor. Biochem Biophys Res Comm 246: 436-440.
Ohigashi T, Mallia CS, McGary E, Scandurro AB, Rondon IJ, Fisher JW, Beckman BS. (1999) Protein kinase C alpha protein expression is necessary for sustained erythropoietin production in human hepatocellular carcinoma (Hep3B) cells exposed to hypoxia. Biochim Biophys Acta 1450(2): 109-18.
Godin DA, Fitzpatrick PC, Scandurro AB, Belafsky PC, Woodworth BA. Amedee RG, Beech DJ, Beckman BS. (2000) PH20: a novel tumor marker for laryngeal cancer. Arch Otolaryngol Head Neck Surg 126(3): 402-4.
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