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Inhibition of human umbilical vein endothelial cell proliferation by the CXC chemokine, platelet factor 4 (PF4), is associated with impaired downregulation of p21(Cip1/WAF1).
- Source :
-
Blood [Blood] 1999 Jan 01; Vol. 93 (1), pp. 25-33. - Publication Year :
- 1999
-
Abstract
- Human PF4 is a heparin-binding chemokine known to be capable of inhibiting endothelial cell proliferation and angiogenesis. To explore the biological mechanisms responsible for this action, we investigated the effect of PF4 on epidermal growth factor (EGF)-stimulated human umbilical vein endothelial cells (HUVEC), a model system in which stimulation is essentially independent of interaction with cell-surface glycosaminoglycans. Based on previous findings that PF4 blocks endothelial cell cycle entry and progression into S phase, we studied the molecular mechanism(s) of PF4 interference with cell cycle machinery. PF4 treatment of EGF-stimulated HUVEC caused a decrease in cyclin E-cyclin-dependent kinase 2 (cdk2) activity with resulting attenuation of retinoblastoma protein phosphorylation. PF4-dependent downregulation of cyclin E-cdk2 activity was associated with increased binding of the cyclin-dependent kinase inhibitor, p21(Cip1/WAF1), to the cyclin E-cdk2 complex. Analysis of total cellular p21(Cip1/WAF1) showed that in the presence of PF4, p21(Cip1/WAF1) levels were sustained at time points when p21(Cip1/WAF1) was no longer detectable in cells stimulated by EGF in the absence of PF4. These findings indicate that PF4 inhibition of HUVEC proliferation in response to EGF is associated with impaired downregulation of p21(Cip1/WAF1) and provide the first evidence for interference with cell cycle mechanisms by a chemokine.
- Subjects :
- Cell Cycle drug effects
Cells, Cultured
Cyclin E metabolism
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinases metabolism
Endothelium, Vascular drug effects
Endothelium, Vascular metabolism
Epidermal Growth Factor pharmacology
Fibroblast Growth Factor 2 pharmacology
Glycosaminoglycans metabolism
Humans
Phosphorylation drug effects
Protein Serine-Threonine Kinases metabolism
Retinoblastoma Protein metabolism
Umbilical Veins
CDC2-CDC28 Kinases
Chemokines, CXC physiology
Cyclins metabolism
Down-Regulation drug effects
Endothelium, Vascular cytology
Growth Inhibitors physiology
Platelet Factor 4 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 93
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 9864142