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Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 25-33
RAPID COMMUNICATION
Inhibition of Human Umbilical Vein Endothelial Cell Proliferation by
the CXC Chemokine, Platelet Factor 4 (PF4), Is Associated With
Impaired Downregulation of p21Cip1/WAF1
Grazia Gentilini,
Nancy E. Kirschbaum,
James A. Augustine,
Richard
H. Aster, and
Gian Paolo Visentin
From the Blood Research Institute, The Blood Center of Southeastern
Wisconsin and the Departments of Medicine and Pathology, Medical
College of Wisconsin, Milwaukee.
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,
p21Cip1/WAF1, to the cyclin E-cdk2 complex. Analysis of
total cellular p21Cip1/WAF1 showed that in the presence of
PF4, p21Cip1/WAF1 levels were sustained at time points when
p21Cip1/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 p21Cip1/WAF1 and provide the
first evidence for interference with cell cycle mechanisms by a
chemokine.
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