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Suppression of p53 activity and p21WAF1/CIP1 expression by vascular cell integrin alphaVbeta3 during angiogenesis

S Strömblad1, J C Becker, M Yebra

  • 1Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.

The Journal of Clinical Investigation
|July 15, 1996
PubMed

Insights

Integrin alphavbeta3 antagonists trigger p53 activity, leading to apoptosis in endothelial cells and blocking tumor growth. Ligation of this integrin promotes cell survival by suppressing p53 and the bax pathway during angiogenesis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Cellular DNA synthesis can conflict with p53 activity, inducing apoptosis.
  • Endothelial cell apoptosis during angiogenesis, triggered by integrin alphavbeta3 antagonists, inhibits tumor growth by causing blood vessel regression.

Purpose of the Study:

  • To investigate the role of integrin alphavbeta3 ligation in regulating endothelial cell survival and p53 activity during angiogenesis.
  • To determine how alphavbeta3 antagonists affect p53 signaling and downstream effectors in angiogenic endothelial cells.

Main Methods:

  • In vivo administration of alphavbeta3 antagonists during angiogenesis.
  • In vitro studies on human endothelial cells to assess the effect of alphavbeta3 ligation state on p53 activity and cell death pathways.
  • Analysis of p53, p21WAF1/CIP1, bcl-2, and bax expression.

Main Results:

  • Alphavbeta3 antagonists activated endothelial cell p53 and increased p21WAF1/CIP1 expression in vivo.
  • In vitro, alphavbeta3 ligation suppressed p53 activity, inhibited p21WAF1/CIP1 expression, and increased the bcl-2/bax ratio, promoting survival.
  • These effects were specific to alphavbeta3, not other integrins.

Conclusions:

  • Integrin alphavbeta3 ligation provides a critical survival signal during angiogenesis, dependent on cell adhesion.
  • This adhesion-dependent signaling inhibits p53 activity, reduces p21WAF1/CIP1 expression, and suppresses the bax cell death pathway, thereby promoting endothelial cell survival.

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