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Updated: Jan 3, 2026
Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
Published on: August 3, 2018
ATF-2 and Tpl2 regulation of endothelial cell cycle progression and apoptosis
Gareth W Fearnley1, Antony M Latham1, Monica Hollstein2
1School of Molecular & Cellular Biology, University of Leeds, UK.
Abstract:
Cells respond to soluble and membrane-bound factors to activate signalling cascades that control cell proliferation and cell death. Vascular endothelial growth factor A (VEGF-A) is a soluble ligand that modulates a variety of cellular responses including cell proliferation and apoptosis. It is not well understood how VEGF-A signalling pathways regulate cell proliferation and cell death. To address this, we examined VEGF-A-regulated signalling pathways in the cytosol and nucleus and functional requirement for such cellular responses. The VEGF-A-regulated transcription factor, ATF-2, is required for cell cycle proteins such as p53, p21 and Cyclin D1. A cytosolic serine/threonine protein kinase (Tpl2) modulates ATF-2-regulated effects on the endothelial cell cycle. Such regulatory effects impact on endothelial cell proliferation, cell viability and apoptosis. These cellular effects influence complex cell-based organisation such as endothelial tubulogenesis. Our study now provides a framework for incorporating VEGF-A-stimulated signalling events from the cytosol to the nucleus which helps to understand how cell proliferation and apoptosis are controlled.
Insights
Vascular Endothelial Growth Factor A (VEGF-A) signaling regulates cell proliferation and apoptosis. This study reveals how VEGF-A pathways in the cytosol and nucleus control cell cycle proteins and endothelial cell functions.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Cellular responses to external factors like VEGF-A are crucial for proliferation and apoptosis.
- VEGF-A signaling pathways' roles in regulating cell proliferation and death remain incompletely understood.
- Understanding these pathways is vital for cell cycle control and complex cellular processes.
Purpose of the Study:
- To investigate VEGF-A-regulated signaling pathways in both the cytosol and nucleus.
- To elucidate the functional requirements of these pathways in cellular responses.
- To establish a framework for VEGF-A-stimulated signaling from cytosol to nucleus.
Main Methods:
- Analysis of VEGF-A signaling cascades.
- Examination of transcription factor ATF-2 activity.
- Investigation of cytosolic protein kinase Tpl2 function.
- Assessment of effects on cell cycle proteins (p53, p21, Cyclin D1).
Main Results:
- VEGF-A activates the transcription factor ATF-2, which is essential for cell cycle proteins.
- Cytosolic Tpl2 kinase modulates ATF-2's effects on the endothelial cell cycle.
- These signaling events impact endothelial cell proliferation, viability, and apoptosis.
- VEGF-A signaling influences complex cellular organizations like endothelial tubulogenesis.
Conclusions:
- A comprehensive framework for VEGF-A signaling from cytosol to nucleus has been established.
- This framework clarifies the mechanisms controlling cell proliferation and apoptosis.
- The findings provide insights into endothelial cell behavior and regulation.
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