Faculty Collaboration Database

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). Blood 1999 Jan 01;93(1):25-33

Date

12/24/1998

Pubmed ID

9864142

Scopus ID

2-s2.0-0032910176 (requires institutional sign-in at Scopus site)   66 Citations

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.

Author List

Gentilini G, Kirschbaum NE, Augustine JA, Aster RH, Visentin GP

MESH terms used to index this publication - Major topics in bold

CDC2-CDC28 Kinases
Cell Cycle
Cells, Cultured
Chemokines, CXC
Cyclin E
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinases
Cyclins
Down-Regulation
Endothelium, Vascular
Epidermal Growth Factor
Fibroblast Growth Factor 2
Glycosaminoglycans
Growth Inhibitors
Humans
Phosphorylation
Platelet Factor 4
Retinoblastoma Protein
Umbilical Veins