TGF-β1 induces endothelial cell apoptosis by shifting VEGF activation of p38MAPK from the prosurvival p38β to proapoptotic p38α

Giovanni Ferrari, Vitaly Terushkin, Martin J. Wolff, Xiaodong Zhang, Cristina Valacca, Paolo Poggio, Giuseppe Pintucci, Paolo Mignatti

Research output: Contribution to journalArticle

Abstract

TGF-β1 and VEGF, both angiogenesis inducers, have opposing effects on vascular endothelial cells. TGF-β1 induces apoptosis; VEGF induces survival. We have previously shown that TGF-β1 induces endothelial cell expression of VEGF, which mediates TGF-β1 induction of apoptosis through activation of p38 mitogen-activated protein kinase (MAPK). Because VEGF activates p38MAPK but protects the cells from apoptosis, this finding suggested that TGF-β1 converts p38MAPK signaling from prosurvival to proapoptotic. Four isoforms of p38MAPK- α, β, γ, and δ - have been identified. Therefore, we hypothesized that different p38MAPK isoforms control endothelial cell apoptosis or survival, and that TGF-β1 directs VEGF activation of p38MAPK from a prosurvival to a proapoptotic isoform. Here, we report that cultured endothelial cells express p38α, β, and γ. VEGF activates p38β, whereas TGF-β1 activates p38α. TGF-β1 treatment rapidly induces p38α activation and apoptosis. Subsequently, p38α activation is downregulated, p38β is activated, and the surviving cells become refractory to TGF-β1 induction of apoptosis and proliferate. Gene silencing of p38α blocks TGF-β1 induction of apoptosis, whereas downregulation of p38β or p38γ expression results in massive apoptosis. Thus, in endothelial cells p38α mediates apoptotic signaling, whereas p38β and p38γ transduce survival signaling. TGF-β1 activation of p38α is mediated by VEGF, which in the absence of TGF-β1 activates p38β. Therefore, these results show that TGF-β1 induces endothelial cell apoptosis by shifting VEGF signaling from the prosurvival p38β to the proapoptotic p38α.

Original languageEnglish
Pages (from-to)605-614
Number of pages10
JournalMolecular Cancer Research
Volume10
Issue number5
DOIs
Publication statusPublished - May 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Fingerprint Dive into the research topics of 'TGF-β1 induces endothelial cell apoptosis by shifting VEGF activation of p38<sup>MAPK</sup> from the prosurvival p38β to proapoptotic p38α'. Together they form a unique fingerprint.

  • Cite this