Vanadium-induced apoptosis of HaCaT cells is mediated by c-fos and involves nuclear accumulation of clusterin

Soultana Markopoulou, Evangelos Kontargiris, Christina Batsi, Theodore Tzavaras, Ioannis Trougakos, David A. Boothman, Efstathios S. Gonos, Evangelos Kolettas

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Vanadium exerts a variety of biological effects, including antiproliferative responses through activation of the respective signaling pathways and the generation of reactive oxygen species. As epidermal cells are exposed to environmental insults, human keratinocytes (HaCaT) were used to investigate the mechanism of the antiproliferative effects of vanadyl(IV) sulfate (VOSO4). Treatment of HaCaT cells with VOSO4 inhibited proliferation and induced apoptosis in a dose-dependent manner. Inhibition of proliferation was associated with downregulation of cyclins D1 and E, E2F1, and the cyclin-dependent kinase inhibitors p21Cip1/Waf1 and p27Kip1. Induction of apoptosis correlated with upregulation of the c-fos oncoprotein, changes in the expression of clusterin (CLU), an altered ratio of antiapoptotic to proapoptotic Bcl-2 protein family members, and poly(ADP-ribose) polymerase-1 cleavage. Forced overexpression of c-fos induced apoptosis in HaCaT cells that correlated with secretory CLU downregulation and upregulation of nuclear CLU (nCLU), a pro-death protein. Overexpression of Bcl-2 protected HaCaT cells from vanadium-induced apoptosis, whereas secretory CLU overexpression offered no cytoprotection. In contrast, nCLU sensitized HaCaT cells to apoptosis. Our data suggest that vanadium-mediated apoptosis was promoted by c-fos, leading to alterations in CLU isoform processing and induction of the pro-death nCLU protein.

Original languageEnglish (US)
Pages (from-to)3784-3799
Number of pages16
JournalFEBS Journal
Volume276
Issue number14
DOIs
StatePublished - Jul 2009

Keywords

  • Apoptosis
  • Bcl-2
  • C-fos
  • Clusterin (CLU)
  • Vanadyl(IV) sulfate

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Markopoulou, S., Kontargiris, E., Batsi, C., Tzavaras, T., Trougakos, I., Boothman, D. A., Gonos, E. S., & Kolettas, E. (2009). Vanadium-induced apoptosis of HaCaT cells is mediated by c-fos and involves nuclear accumulation of clusterin. FEBS Journal, 276(14), 3784-3799. https://doi.org/10.1111/j.1742-4658.2009.07093.x