Thrombospondin 2 regulates cell proliferation induced by Rac1 redox-dependent signaling

Neuza Lopes, David Gregg, Sanjay Vasudevan, Hamdy Hassanain, Pascal Goldschmidt-Clermont, Hervé Kovacic

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42 Scopus citations

Abstract

Thrombospondin 2 (TSP2) is a matricellular protein controlling the apoptosis-proliferation balance in endothelial cells. Little is known about its transcriptional regulation compared with that of TSP1. We found that overexpression of a constitutively active mutant of Rac (RacV12) specifically increases TSP2 mRNA levels without affecting TSP1 in human aortic endothelial cells (HAEC). Moreover, TSP2 induction by RacV12 is dependent upon reactive oxygen species (ROS) production, as gp91ds-tat peptide, an inhibitor of NADPH oxidase, and the flavoprotein inhibitor diphenylene iodinium (DPI) block TSP2 synthesis. Furthermore, we found that increasing RacV12 expression results in a biphasic proliferative curve, with proliferation initially increasing as RacV12 expression increases and then returning to levels less than that of control cells at higher expression. This growth inhibition is mediated by TSP2, as either DPI treatment, which blocks TSP2 synthesis, or pan-TSP blocking antibodies restore the proliferative ability of HAEC with high expression. Mechanistically, we show that the effect of TSP2 on cell proliferation is independent of the antiangiogenic TSP2 Hep1 sequence, which is capable of altering actin cytoskeletal reorganization but not proliferation in our experimental conditions. Finally, we show in vivo that Rac-induced TSP2 expression is observed in the aorta of transgenic mice selectively expressing RacV12 in smooth muscle cells. These results identify Rac-induced ROS as a new pathway involved in the regulation of TSP2 expression.

Original languageEnglish (US)
Pages (from-to)5401-5408
Number of pages8
JournalMolecular and cellular biology
Volume23
Issue number15
DOIs
StatePublished - Aug 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Lopes, N., Gregg, D., Vasudevan, S., Hassanain, H., Goldschmidt-Clermont, P., & Kovacic, H. (2003). Thrombospondin 2 regulates cell proliferation induced by Rac1 redox-dependent signaling. Molecular and cellular biology, 23(15), 5401-5408. https://doi.org/10.1128/MCB.23.15.5401-5408.2003