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The antiangiogenic agent TNP-470 requires p53 and p21CIP/WAF for endothelial cell growth arrest
1Departments of Molecular, Cellular, and Developmental Biology, and Pharmacology, Yale University, New Haven, CT 06520-8103, USA.
Abstract:
Targeting the endothelial cell cycle as an antiangiogenic strategy has been difficult given the ubiquitous expression of critical cell cycle regulators. Here, we show that the antiangiogenic drug TNP-470 displays striking cell-type specificity insofar as it induces the expression of p21(CIP/WAF), a cyclin-dependent kinase inhibitor, in endothelial cells but not in embryonic or adult fibroblasts. Moreover, primary endothelial cells isolated from p53(-/-) and p21(CIP/WAF-/-) mice are resistant to the cytostatic activity of TNP-470. We also demonstrate that p21(CIP/WAF-/-) mice are resistant to the antiangiogenic activity of TNP-470 in the basic fibroblast growth factor corneal micropocket angiogenesis assay. We conclude that TNP-470 induces p53 activation through a unique mechanism in endothelial cells leading to p21(CIP/WAF) expression and subsequent growth arrest.
Insights
The anti-angiogenic drug TNP-470 specifically targets endothelial cells by inducing p21 expression, a key cell cycle inhibitor. This targeted approach offers a promising strategy for anti-angiogenesis therapies.
Area of Science:
- Molecular Biology
- Cell Biology
- Pharmacology
Background:
- Targeting the endothelial cell cycle for anti-angiogenesis is challenging due to widespread cell cycle regulator expression.
- Developing cell-type specific anti-angiogenic strategies is crucial.
Purpose of the Study:
- To investigate the cell-type specificity of the anti-angiogenic drug TNP-470.
- To elucidate the mechanism by which TNP-470 exerts its anti-angiogenic effects.
Main Methods:
- Assessing TNP-470's effect on p21(CIP/WAF) expression in endothelial cells versus fibroblasts.
- Evaluating TNP-470's cytostatic activity in primary endothelial cells from p53(-/-) and p21(CIP/WAF-/-) mice.
- Testing TNP-470's anti-angiogenic activity in p21(CIP/WAF-/-) mice using a corneal micropocket assay.
Main Results:
- TNP-470 specifically induces p21(CIP/WAF) expression in endothelial cells, not fibroblasts.
- Endothelial cells and mice lacking p53 or p21 are resistant to TNP-470's effects.
- TNP-470's anti-angiogenic activity is dependent on p21 expression.
Conclusions:
- TNP-470 exhibits cell-type specific anti-angiogenic properties by uniquely activating p53 in endothelial cells.
- This activation leads to p21(CIP/WAF) induction, resulting in endothelial cell growth arrest.
- The findings highlight a novel mechanism for targeted anti-angiogenesis therapy.