Abstract
Recent evidence has established different functions for the tumor suppressor protein, p16(INK4A) aside from controlling the cell cycle. Here we report that cdk4/6 inhibition blocked both human umbilical vein endothelial cells (HUVEC) spreading on a vitronectin matrix and HUVEC migration on vitronectin. p16 can also act as an anti-angiogenic molecule in vitro since HUVEC and HMEC cells transfected with Ad-p16 or treated with Antennapedia p16 peptides are unable to differentiate on a Matrigel matrix. Both, p16, cyclin D1, cdk4 and cdk6 were immuno-colocalized with Ezrin, Rac, Vinculin, alphav-integrin, and FAK proteins in the ruffles and lamellipodia of migratory cells. Our results indicate that p16 is a key component of a new cytoplasmic pathway controlling angiogenesis of endothelial cells via the alphavbeta3-integrin-mediated migration.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Membrane / metabolism
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Cell Movement / physiology*
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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Cyclin-Dependent Kinase Inhibitor p16 / physiology*
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Endothelium, Vascular / cytology*
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Endothelium, Vascular / drug effects
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Enzyme Inhibitors / pharmacology
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Focal Adhesion Protein-Tyrosine Kinases / metabolism
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Humans
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Integrin alphaVbeta3 / metabolism
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Neovascularization, Physiologic / physiology*
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Pseudopodia / metabolism*
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Subcellular Fractions / enzymology
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Subcellular Fractions / metabolism
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Vinculin / metabolism
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rac GTP-Binding Proteins / metabolism
Substances
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Cyclin-Dependent Kinase Inhibitor p16
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Enzyme Inhibitors
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Integrin alphaVbeta3
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Vinculin
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Focal Adhesion Protein-Tyrosine Kinases
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Cyclin-Dependent Kinases
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rac GTP-Binding Proteins