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Published on: June 15, 2017
Cell type-specific regulation of CCN2 protein expression by PI3K-AKT-FoxO signaling
Jana Samarin1, Iwona Cicha, Margarete Goppelt-Struebe
1Department of Nephrology and Hypertension, Medical Clinic 4, University of Erlangen-Nürnberg, University Hospital Erlangen, 91054, Erlangen, Germany.
Abstract:
The biological activity of connective tissue growth factor (CTGF, CCN2) is regulated at the level of intracellular signaling leading to gene expression, and by its extracellular interaction partners which determine the functional outcome of CCN2 action. In this overview, we summarize the data which provide evidence that one of the major signaling pathways, phosphatidylinositol-3 kinase (PI3K)-AKT signaling, shows a remarkable cell type-dependence in terms of regulation of CCN2 expression. In smooth muscle cells, fibroblasts, and epithelial cells, inhibition of this pathway either reduced CCN2 expression or was not involved in CCN2 gene expression depending on the stimulus used. In microvascular endothelial cells by contrast, activation of PI3K-AKT signaling was inversely related to CCN2 expression. Upregulation of CCN2 upon inhibition of PI3K-AKT was also observed in primary cultures of human endothelial cells (HUVEC) exposed to laminar flow in an in vitro flow-through system. In different types of endothelial cells, FoxO transcription factors, which are negatively regulated by AKT, were identified as potent activators of CCN2 gene expression. In HUVEC, we observed a correlation between enhanced nuclear localization of FoxO1 and increased synthesis of CCN2 protein in areas of non-uniform shear stress. These data indicate that FoxO proteins are key regulators of CCN2 gene expression which determine the effect of PI3K-AKT activation in terms of CCN2 regulation. Short summary Phosphatidylinositol-3 kinase (PI3K)-AKT signaling shows a remarkable cell type-dependence in terms of regulation of CCN2 expression. In endothelial cells activation of PI3K - AKT signaling was inversely related to CCN2 expression. FoxO transcription factors, which are negatively regulated by AKT, were identified as potent activators of CCN2 gene expression.
Insights
Connective tissue growth factor (CTGF, CCN2) regulation varies by cell type. In endothelial cells, PI3K-AKT signaling inversely affects CCN2 expression, with FoxO transcription factors acting as key activators.
Area of Science:
- Cellular and Molecular Biology
- Biochemistry
- Physiology
Background:
- Connective tissue growth factor (CTGF, CCN2) biological activity is modulated by intracellular signaling and extracellular interactions.
- The phosphatidylinositol-3 kinase (PI3K)-AKT signaling pathway plays a critical role in regulating gene expression, including that of CCN2.
- Cell type-specific differences in CCN2 regulation by PI3K-AKT signaling are increasingly recognized.
Purpose of the Study:
- To investigate the cell type-dependent regulation of CCN2 expression by the PI3K-AKT signaling pathway.
- To elucidate the role of FoxO transcription factors in mediating CCN2 gene expression in endothelial cells.
- To understand the interplay between PI3K-AKT signaling, FoxO factors, and CCN2 regulation under varying shear stress conditions.
Main Methods:
- Analysis of CCN2 expression in various cell types (smooth muscle cells, fibroblasts, epithelial cells, microvascular endothelial cells, HUVEC) under different PI3K-AKT signaling modulations.
- In vitro flow-through system using HUVEC exposed to laminar flow.
- Assessment of FoxO transcription factor localization (nuclear vs. cytoplasmic) and its correlation with CCN2 synthesis.
Main Results:
- PI3K-AKT signaling exhibits cell type-dependent effects on CCN2 expression.
- In endothelial cells, PI3K-AKT activation is inversely correlated with CCN2 expression, while inhibition upregulates CCN2.
- FoxO transcription factors, negatively regulated by AKT, were identified as potent activators of CCN2 gene expression in endothelial cells, with enhanced nuclear localization correlating with increased CCN2 synthesis under non-uniform shear stress.
Conclusions:
- FoxO transcription factors are key regulators of CCN2 gene expression, particularly in endothelial cells.
- The PI3K-AKT pathway's effect on CCN2 expression is significantly influenced by the cellular context and the activity of FoxO transcription factors.
- Understanding these regulatory mechanisms is crucial for deciphering CCN2's role in endothelial cell function and response to mechanical stimuli.
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