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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

Blood, ISSN: 0006-4971, Vol: 93, Issue: 1, Page: 25-33
1999
  • 65
    Citations
  • 0
    Usage
  • 15
    Captures
  • 0
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    65
    • Citation Indexes
      65
  • Captures
    15

Article Description

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.

Bibliographic Details

Grazia Gentilini; Nancy E. Kirschbaum; James A. Augustine; Richard H. Aster; Gian Paolo Visentin

American Society of Hematology

Biochemistry, Genetics and Molecular Biology; Immunology and Microbiology; Medicine

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