Angiogenesis, the formation of new blood vessels, is a prerequisite of solid tumor growth. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is produced by tumor tissues in vivo and various tumor cell lines in vitro and acts specifically on vascular endothelial cells to induce angiogenesis. Upregulated expression of VEGF and its receptors have been found in many tumor types. Mutants of tumor suppressor p53 protein can stimulate VEGF expression. Previous studies showed that okadaic acid, one of the tumor promoters, can induce angiogenesis. In addition, okadaic acid regulates p53 protein activities by modulating its phosphorylation status. It has been suggested that there is a resemblance of modulation of p53 activities by p53 hyperphosphorylation and p53 mutations. To date, most attention has been concentrated on the anatomical sites of VEGF expression and how endothelial cells respond to this factor in both physiological and pathological conditions. In contrast, this proposal focuses on the regulation of VEGF expression by tumor cells and particularly, the role of the p53 protein and its phosphorylation in this regulation. The following specific aims will be pursued: 1). determine the role of the hyperphosphorylation of wild type p53 or mutant p53 in regulation of VEGF expression by non-small-cell lung cancer cells. 2) identify the protein kinase(s) that phosphorylate p53 protein in response to okadaic acid and thereby regulate VEGF expression by the tumor cells. 3). define the okadaic acid/modified p53 responsive element in VEGF promoter. This should help to unravel regulatory mechanisms of tumor angiogenesis, and to develop more effective therapeutic drugs and treatments targeting tumor angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL009391-03
Application #
2735006
Study Section
Pathology A Study Section (PTHA)
Project Start
1998-07-01
Project End
Budget Start
1998-07-01
Budget End
1999-03-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Nishikawa, R; Cheng, S Y; Nagashima, R et al. (1998) Expression of vascular endothelial growth factor in human brain tumors. Acta Neuropathol (Berl) 96:453-62
Cheng, S Y; Nagane, M; Huang, H S et al. (1997) Intracerebral tumor-associated hemorrhage caused by overexpression of the vascular endothelial growth factor isoforms VEGF121 and VEGF165 but not VEGF189. Proc Natl Acad Sci U S A 94:12081-7