The Ras-related protein AGS1/RASD1 suppresses cell growth
activation; AGS1; apoptosis; binding protein; Biochemistry & Molecular Biology; cancer; Cell Biology; coupled receptors; Dexras1; Dexras1; G protein; gene; Genetics &; Heredity; hormone; identification; Integration; Oncology; RASD1; signal-transduction
AGS1/RASD1 is a Ras-related protein identified as a dexamethasone-inducible cDNA and as a signal regulator in various functional and protein-interaction screens. As an initial approach to define the role of AGS1/RASD1 as a Ras-family member, we determined its influence on cell growth/survival. In clonogenic assays with NIH-3T3 murine fibroblast cells, the MCF-7 human breast cancer cell line and the human lung adenocarcinoma cell line A549, AGS1/RASD1 markedly diminished the number of G418-resistant colonies, whereas the Ras subgroup member K-Ras was without effect. A549 cell infection with adenovirus engineered to express AGS1/RASD1 (Ad.AGS1) inhibited log phase growth in vitro and increased the percentage of cells undergoing apoptosis. The anti-growth action was also observed in vivo as the expression of AGS1/RASD1 inhibited the subcutaneous tumor growth of A549 cells in athymic nude mice. These data indicate that AGS1/RASD1, a member of the Ras superfamily of small G-proteins that often promotes cell growth and tumor expansion, plays an active role in preventing aberrant cell growth.
Vaidyanathan G; Cismowski M J; Wang G S; Vincent T S; Brown K D; Lanier S M
Oncogene
2004
2004-07
Journal Article
<a href="http://doi.org/10.1038/sj.onc.1207774" target="_blank" rel="noreferrer noopener">10.1038/sj.onc.1207774</a>
Thrombospondin-4 mediates TGF-beta-induced angiogenesis.
Angiogenesis Inducing Agents/*metabolism; Animals; Cell Movement/drug effects; Cell Proliferation/drug effects; Cells; Chick Embryo; Cultured; Endothelium; Female; Gene Expression Regulation/drug effects; Humans; Inbred C57BL; Male; Mice; Muscle; Neovascularization; Pathologic/drug therapy/metabolism/*pathology; Signal Transduction/drug effects; Smooth; Thrombospondins/*physiology; Transforming Growth Factor beta/*pharmacology; Vascular/drug effects/metabolism/*pathology
TGF-beta is a multifunctional cytokine affecting many cell types and implicated in tissue remodeling processes. Due to its many functions and cell-specific effects, the consequences of TGF-beta signaling are process-and stage-dependent, and it is not uncommon that TGF-beta exerts distinct and sometimes opposing effects on a disease progression depending on the stage and on the pathological changes associated with the stage. The mechanisms underlying cell- and process-specific effects of TGF-beta are poorly understood. We are describing a novel pathway that mediates induction of angiogenesis in response to TGF-beta1. We found that in endothelial cells (EC) thrombospondin-4 (TSP-4), a secreted extracellular matrix (ECM) protein, is upregulated in response to TGF-beta1 and mediates the effects of TGF-beta1 on angiogenesis. Upregulation of TSP-4 does not require the synthesis of new protein, is not caused by decreased secretion of
Muppala S; Xiao R; Krukovets I; Verbovetsky D; Yendamuri R; Habib N; Raman P; Plow E; Stenina-Adognravi O
Oncogene
2017
2017-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/onc.2017.140" target="_blank" rel="noreferrer noopener">10.1038/onc.2017.140</a>
Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy.
Animals; Calcium Signaling/genetics; Carcinoma; Cell Line; Cell Proliferation/drug effects; Cisplatin/administration & dosage; Endothelium; Gene Expression Regulation; Humans; Leucine/administration & dosage/analogs & derivatives; Lewis Lung/drug therapy/*genetics/pathology; Mice; Neoplastic/drug effects; Neovascularization; Pathologic/drug therapy/*genetics/pathology; Sulfonamides/administration & dosage; TRPV Cation Channels/agonists/biosynthesis/*genetics; Tumor; Vascular Endothelial Growth Factor A/genetics; Vascular/drug effects/*pathology
Tumor vessels are characterized by abnormal morphology and hyperpermeability that together cause inefficient delivery of chemotherapeutic agents. Although vascular endothelial growth factor has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the regulation of tumor vasculature or tumor endothelial cell (TEC) function is not known. Here we show that the mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TECs exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards extracellular matrix stiffness, increased migration and abnormal angiogenesis by TEC. Further, syngeneic tumor experiments revealed that the absence of TRPV4 induced increased vascular density, vessel diameter and reduced pericyte coverage resulting in enhanced tumor growth in TRPV4 knockout mice. Importantly, overexpression or pharmacological activation of TRPV4 restored aberrant TEC mechanosensitivity, migration and normalized abnormal angiogenesis in vitro by modulating Rho activity. Finally, a small molecule activator of TRPV4, GSK1016790A, in combination with anticancer drug cisplatin, significantly reduced tumor growth in wild-type mice by inducing vessel maturation. Our findings demonstrate TRPV4 channels to be critical regulators of tumor angiogenesis and represent a novel target for anti-angiogenic and vascular normalization therapies.
Adapala R K; Thoppil R J; Ghosh K; Cappelli H C; Dudley A C; Paruchuri S; Keshamouni V; Klagsbrun M; Meszaros J G; Chilian W M; Ingber D E; Thodeti C K
Oncogene
2016
2016-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/onc.2015.83" target="_blank" rel="noreferrer noopener">10.1038/onc.2015.83</a>