Tumors require the formation of new blood vessels termed, 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 successfully 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.

VEGF, 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 (Scandurro and Beckman, 1998). 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 in understanding oxygen-sensing at the post-transcriptional level with the hypothesis that ERBP30 and ERBP70 are common post-transcriptional factors involved in oxygen-sensing.

LaMarca, Heather L., Anne B. Nelson, Aline B. Scandurro, Guy St. J. Whitley, Cindy A.
Morris. 2005. Human cytomegalovirus-induced inhibition of cytotrophoblast invasion in a first trimester extravillous cytotrophoblast cell line. Placenta in press. Abstract

Weldon, C. B., A. McKee, B. M. Collins-Burow, L. I. Melnik, A. B. Scandurro, J. A. McLachlan, M. E. Burow, B. S. Beckman. 2005. PKC-mediated survival signaling in breast carcinoma cells: a role for MEK1-AP1 signaling. Int. J. Oncol. 26(3):763-8. Abstract

Frigo, D. E., Y. Tang, B. S. Beckman, A. B. Scandurro, J. Alam, M. E. Burow, J. A. McLachlan. 2004. Mechanism of AP-1-mediated gene expression by select organochlorines through the p38 MAPK pathway. Carcinogenesis. 25(2):249-61. Abstract

Figueroa, Y. G., A. K. Chan, R. Ibrahim, Y. Tang, M. E. Burow, J. Alam, A. B. Scandurro, B. S. Beckman. 2002. NF-kappaB plays a key role in hypoxia-inducible factor-1-regulated erythropoietin gene expression. Exp. Hematol. 30(12):1419-27. Abstract

Weldon, C. B., A. B. Scandurro, K. W. Rolfe, J. L. Clayton, S. Elliott, N. N. Butler, L. I. Melnik, J. Alam, J. A. McLachlan, B. M. Jaffe, B. S. Beckman, M. E. Burow. 2002. Identification of mitogen-activated protein kinase kinase as a chemoresistant pathway in MCF-7 cells by using gene expression microarray. Surgery.132(2):293-301. Abstract

Contact Information: Aline B. Scandurro, Ph.D. Department of Microbiology and Immunology Tulane University Health Sciences Center 1430 Tulane Avenue New Orleans, LA 70112-2699 phone: (504) 988-41934 fax: (504) 988-5144   alibscan@tulane.edu

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