PUBLICATION
TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1α activity
- Authors
- Stantic, M., Sakil, H.A., Zirath, H., Fang, T., Sanz, G., Fernandez-Woodbridge, A., Marin, A., Susanto, E., Mak, T.W., Arsenian Henriksson, M., Wilhelm, M.T.
- ID
- ZDB-PUB-170214-244
- Date
- 2015
- Source
- Proceedings of the National Academy of Sciences of the United States of America 112: 220-5 (Journal)
- Registered Authors
- Keywords
- HIF-1 alpha, angiogenesis, p73, tumor microenvironment, vascular permeability
- MeSH Terms
-
- Breast Neoplasms/blood supply*
- Breast Neoplasms/metabolism*
- Breast Neoplasms/pathology
- Female
- Zebrafish
- DNA-Binding Proteins/metabolism*
- Tumor Suppressor Proteins/metabolism*
- Nuclear Proteins/metabolism*
- Gene Expression Regulation
- Inflammation/genetics
- Inflammation/pathology
- Cytokines/metabolism*
- Animals
- Cadherins/metabolism
- Permeability
- Cell Line, Transformed
- Neovascularization, Pathologic/metabolism*
- Neovascularization, Pathologic/pathology
- Cell Hypoxia
- Humans
- Protein Isoforms/metabolism
- Mice
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*
- Endothelial Cells/metabolism
- Tumor Protein p73
- Cell Proliferation
- Neovascularization, Physiologic
- Angiogenesis Inducing Agents/metabolism*
- PubMed
- 25535357 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Stantic, M., Sakil, H.A., Zirath, H., Fang, T., Sanz, G., Fernandez-Woodbridge, A., Marin, A., Susanto, E., Mak, T.W., Arsenian Henriksson, M., Wilhelm, M.T. (2015) TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1α activity. Proceedings of the National Academy of Sciences of the United States of America. 112:220-5.
Abstract
The p53-family member TAp73 is known to function as a tumor suppressor and regulates genomic integrity, cellular proliferation, and apoptosis; however, its role in tumor angiogenesis is poorly understood. Here we demonstrate that TAp73 regulates tumor angiogenesis through repression of proangiogenic and proinflammatory cytokines. Importantly, loss of TAp73 results in highly vascularized tumors, as well as an increase in vessel permeability resulting from disruption of vascular endothelial-cadherin junctions between endothelial cells. In contrast, loss of the oncogenic p73 isoform ΔNp73 leads to reduced blood vessel formation in tumors. Furthermore, we show that up-regulated ΔNp73 levels are associated with increased angiogenesis in human breast cancer and that inhibition of TAp73 results in an accumulation of HIF-1α and up-regulation of HIF-1α target genes. Taken together, our data demonstrate that loss of TAp73 or ΔNp73 up-regulation activates the angiogenic switch that stimulates tumor growth and progression.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping