The goal of this proposal is to investigate the molecular mechanisms controlling angiogenesis, which is critical for sustaining tumor growth. BMK1/ERK5 is a newer member of mammalian MAP kinase family and is activated by angiogenic growth factors. Recently, data generated from our conditional knockout mice of BMK1 revealed that BMK1is critical for angiogenesis not only during the embryonic stage but also in adulthood, most likely through its role in endothelial cells (EC).To investigate and to define the function and molecular actions of BMK1pathway in EC and in angiogenesis, we propose (1) to investigate the signaling pathway(s) that interacts with or is regulated by the BMK1cascade in endothelial cells and (2) to explore the mechanism of action of the BMK1 cascade during angiogenesis. These proposed studies should provide new information on the regulatory mechanisms of neovascularization by which we hope to identify novel and important targets for a more effective and specific therapeutic intervention for human cancer through inhibiting tumor-associated angiogenesis

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA079871-10
Application #
7763924
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Ault, Grace S
Project Start
2000-04-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
10
Fiscal Year
2010
Total Cost
$315,569
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Deng, Xianming; Elkins, Jonathan M; Zhang, Jinwei et al. (2013) Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones. Eur J Med Chem 70:758-67
Yang, Q; Liao, L; Deng, X et al. (2013) BMK1 is involved in the regulation of p53 through disrupting the PML-MDM2 interaction. Oncogene 32:3156-64
Chen, Runqiang; Yang, Qingkai; Lee, Jiing-Dwan (2012) BMK1 kinase suppresses epithelial-mesenchymal transition through the Akt/GSK3ýý signaling pathway. Cancer Res 72:1579-87
Yang, Qingkai; Lee, Jiing-Dwan (2011) Targeting the BMK1 MAP kinase pathway in cancer therapy. Clin Cancer Res 17:3527-32
Deng, Xianming; Dzamko, Nicolas; Prescott, Alan et al. (2011) Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nat Chem Biol 7:203-5
Yang, Qingkai; Deng, Xianming; Lu, Bingwen et al. (2010) Pharmacological inhibition of BMK1 suppresses tumor growth through promyelocytic leukemia protein. Cancer Cell 18:258-67
Chen, Run-Qiang; Yang, Qing-Kai; Lu, Bing-Wen et al. (2009) CDC25B mediates rapamycin-induced oncogenic responses in cancer cells. Cancer Res 69:2663-8
Chen, Yanling; Lu, Bingwen; Yang, Qingkai et al. (2009) Combined integrin phosphoproteomic analyses and small interfering RNA--based functional screening identify key regulators for cancer cell adhesion and migration. Cancer Res 69:3713-20
Chen, Run-Qiang; Yang, Qing-Kai; Chen, Yan-Ling et al. (2009) Kinome siRNA screen identifies SMG-1 as a negative regulator of hypoxia-inducible factor-1alpha in hypoxia. J Biol Chem 284:16752-8
Zhu, J-H; Chen, R; Yi, W et al. (2008) Protein tyrosine phosphatase PTPN13 negatively regulates Her2/ErbB2 malignant signaling. Oncogene 27:2525-31

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