Vascular endothelial cell growth factor (VEGF) is a mitogen that promotes angiogenesis associated with physiological and pathological processes (cancer, rheumatoid arthritis, retinopathies). The first step in VEGF action is binding to either of two receptor tyrosine kinases, Flk-1 and Flt-1. The roles of these receptors in mediating cellular responses to VEGF have not been well defined nor have the signaling pathways that promote the activities of either receptor. Using ribozyme/antisense constructs that specifically target and degrade Flk-1 and Flt-1, they will isolate endothelial cells in which one or the other VEGF receptor has been knocked out. Such cells will be used to define the responses mediated by Flk-1 and Flt-1. From among the transduction pathways associated with VEGF action, they have found that phosphatidylinositol 3-kinase and mitogen activated protein kinases are especially important. The role of these systems in promoting diverse responses induced by VEGF will be defined. Finally, they have found that protein tyrosine phosphatases can positively and negatively regulate VEGF action. The role of such phosphatases, two in particular- SYP and LAR, in modulating VEGF signaling and cellular responses to VEGF will be defined.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA073023-01A1
Application #
2386930
Study Section
Pathology A Study Section (PTHA)
Project Start
1997-09-01
Project End
2002-06-30
Budget Start
1997-09-01
Budget End
1998-06-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Physiology
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Mayo, Lindsey D; Seo, Young Rok; Jackson, Mark W et al. (2005) Phosphorylation of human p53 at serine 46 determines promoter selection and whether apoptosis is attenuated or amplified. J Biol Chem 280:25953-9
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Su, Jing Dong; Mayo, Lindsey D; Donner, David B et al. (2003) PTEN and phosphatidylinositol 3'-kinase inhibitors up-regulate p53 and block tumor-induced angiogenesis: evidence for an effect on the tumor and endothelial compartment. Cancer Res 63:3585-92
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Mayo, L D; Kessler, K M; Pincheira, R et al. (2001) Vascular endothelial cell growth factor activates CRE-binding protein by signaling through the KDR receptor tyrosine kinase. J Biol Chem 276:25184-9
Mayo, L D; Donner, D B (2001) A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A 98:11598-603
Ozes, O N; Akca, H; Mayo, L D et al. (2001) A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proc Natl Acad Sci U S A 98:4640-5
Gustin, J A; Maehama, T; Dixon, J E et al. (2001) The PTEN tumor suppressor protein inhibits tumor necrosis factor-induced nuclear factor kappa B activity. J Biol Chem 276:27740-4
Wu, L W; Mayo, L D; Dunbar, J D et al. (2000) Utilization of distinct signaling pathways by receptors for vascular endothelial cell growth factor and other mitogens in the induction of endothelial cell proliferation. J Biol Chem 275:5096-103

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