Angiogenesis promotes tumor growth and metastasis and is an important therapeutic target in the treatment of cancer. Angiogenesis factors activate transcription factors that control endothelial cell proliferation. RUNX2 is a DNA-binding transcription factor that interacts with the TGFb/Smad family of transcriptional modulators to stimulate cell proliferation and tumor progression. RUNX2 also represses the promoter of p21Cip1, a cyclin-dependent kinase inhibitor, inhibits p21Cip1 protein expression, and reduces TGFb-mediated growth inhibition of endothelial cells. We hypothesize that RUNX2 stimulates angiogenesis and endothelial cell proliferation by promoting cell cycle progression through its inhibition of the TGFb1/Smad pathway and repression of p21Cip1 expression. The following specific aims will test this hypothesis.
SPECIFIC AIM 1 : To establish a role for RUNX2 in stimulating endothelial cell proliferation and promoting angiogenesis in vivo.
SPECIFIC AIM 2 : To define the requirement for RUNX2 expression and phosphorylation in controlling endothelial cell cycle progression and angiogenesis.
SPECIFIC AIM 3 : To determine how RUNX2 promotes cell cycle progression and EC proliferation through inhibition of the TGFb1/Smad pathway and/or the cdk inhibitor, p21Cip1. The goals of this proposal are to define how RUNX2 increases endothelial cell proliferation, to determine how RUNX2 regulates cell cycle progression, and to define the interactions of RUNX2 with Smad signaling components, which regulate p21Cip1 expression. Several molecular approaches will be employed, including siRNA-mediated knockdown of RUNX2, the use of RUNX2-inducible cell lines, and cell cycle regulatory activities of RUNX2. Angiogenesis research may uncover new mechanisms regulating blood vessel formation within tumors and could lead to identification of novel anti-tumor agents or improved drug delivery to tumors. Therefore, the development of anti-angiogenic therapeutic agents that inhibit EC proliferation is highly relevant to the NIH mission to improve public health and is a critical approach that may become important in the treatment of cancer. Although not a topic of this proposal, the strategies and treatments discovered in this study may also be relevant for the treatment of other diseases that depend on angiogenesis and cause significant health problems. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA108846-01A2
Application #
7149602
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Ault, Grace S
Project Start
2006-07-19
Project End
2010-05-31
Budget Start
2006-07-19
Budget End
2007-05-31
Support Year
1
Fiscal Year
2006
Total Cost
$263,588
Indirect Cost
Name
University of Maryland Baltimore
Department
Pathology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Underwood, Karen F; Mochin, Maria T; Brusgard, Jessica L et al. (2013) A quantitative assay to study protein:DNA interactions, discover transcriptional regulators of gene expression, and identify novel anti-tumor agents. J Vis Exp :
Underwood, Karen F; D'Souza, David R; Mochin-Peters, Maria et al. (2012) Regulation of RUNX2 transcription factor-DNA interactions and cell proliferation by vitamin D3 (cholecalciferol) prohormone activity. J Bone Miner Res 27:913-25
Pierce, Adam D; Anglin, Ian E; Vitolo, Michele I et al. (2012) Glucose-activated RUNX2 phosphorylation promotes endothelial cell proliferation and an angiogenic phenotype. J Cell Biochem 113:282-92
D'Souza, David R; Salib, Maryann M; Bennett, Jessica et al. (2009) Hyperglycemia regulates RUNX2 activation and cellular wound healing through the aldose reductase polyol pathway. J Biol Chem 284:17947-55