Cyclin D1 degradation enhances endothelial cell survival upon oxidative stress

Pasquale Fasanaro, Alessandra Magenta, Germana Zaccagnini, Lucia Cicchillitti, Sergio Fucile, Fabrizio Eusebi, Paolo Biglioli, Maurizio C. Capogrossi, Fabio Martelli

Research output: Contribution to journalArticle

Abstract

The understanding of endothelial cell responses to oxidative stress may provide insights into aging mechanisms and into the pathogenesis of numerous cardiovascular diseases. In this study, we examined the regulation and the functional role of cyclin D1, a crucial player in cell proliferation and survival. On H 2O 2 treatment, endothelial cells showed a rapid down-modulation of cyclin D1. Other D-cyclins were similarly regulated, and this decrease was also observed after exposure to other oxidative stress-inducing stimuli, namely 1,3-bis (2 chloroethyl)-1 nitrosourea treatment and ischemia. H 2O 2 treatment induced cyclin D1 ubiquitination followed by proteasome degradation. Phospholipase C inhibition prevented cyclin D1 degradation, and its activation triggered cyclin D1 downmodulation in the absence of oxidative stress. Activated phospholipase C generates inositol-1,4,5-trisphosphate (IP3) and Ca 2+ release from internal stores. We found that both IP3-receptor inhibition and intracellular Ca 2+ chelation prevented cyclin D1 degradation induced by oxidative stress. Furthermore, Ca 2+ increase was transduced by Ca 2+/calmodulin-dependent protein kinase (CaMK). In fact, H 2O 2 stimulated CaMK activity, CaMK inhibitors prevented H 2O 2-induced cyclin D1 down-modulation, and CaMK overexpression induced cyclin D1 degradation. Finally, overriding of cyclin D1 downmodulation via its forced overexpression or via CaMK inhibition increased cell sensitivity to H 2O 2-induced apoptotic cell death. Thus, cyclin D1 degradation enhances endothelial cell survival on oxidative stress.

Original languageEnglish
JournalFASEB Journal
Volume20
Issue number8
DOIs
Publication statusPublished - Jun 2006

Keywords

  • Apoptosis
  • Calcium signaling
  • Endothelium
  • Ubiquitin-proteasome pathway

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

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