Anti-migratory and anti-angiogenic effect of p16: a novel localization at membrane ruffles and lamellipodia in endothelial cells.
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.
Alhaja
Elena
E
Advancell, Barcelona, Catalonia, Spain.
Adan
Jaume
J
Pagan
Roser
R
Mitjans
Francesc
F
Cascalló
Manel
M
Rodríguez
Mercè
M
Noé
Veronique
V
Ciudad
Carlos J
CJ
Mazo
Adela
A
Vilaró
Senén
S
Piulats
Jaume
J
D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011554:Pseudopodia / Q000378:metabolism*; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism; D016596:Vinculin / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D039302:Integrin alphaVbeta3; D016596:Vinculin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D018844:Cyclin-Dependent Kinases; D020744:rac GTP-Binding Proteins