PUBLICATION
TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1? 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
-
- Zebrafish
- Tumor Suppressor Proteins/metabolism*
- Protein Isoforms/metabolism
- Neovascularization, Physiologic
- Tumor Protein p73
- Permeability
- Gene Expression Regulation
- Mice
- Nuclear Proteins/metabolism*
- Cadherins/metabolism
- Cytokines/metabolism*
- Inflammation/genetics
- Inflammation/pathology
- Endothelial Cells/metabolism
- Female
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*
- Breast Neoplasms/blood supply*
- Breast Neoplasms/metabolism*
- Breast Neoplasms/pathology
- Angiogenesis Inducing Agents/metabolism*
- Neovascularization, Pathologic/metabolism*
- Neovascularization, Pathologic/pathology
- DNA-Binding Proteins/metabolism*
- Animals
- Cell Hypoxia
- Humans
- Cell Proliferation
- Cell Line, Transformed
- 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-1? 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 ?Np73 leads to reduced blood vessel formation in tumors. Furthermore, we show that up-regulated ?Np73 levels are associated with increased angiogenesis in human breast cancer and that inhibition of TAp73 results in an accumulation of HIF-1? and up-regulation of HIF-1? target genes. Taken together, our data demonstrate that loss of TAp73 or ?Np73 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