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 H₂O₂ 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. H₂O₂ treatment induced cyclin D1 ubiquitination followed by proteasome degradation. Phospholipase C inhibition prevented cyclin D1 degradation, and its activation triggered cyclin D1 down-modulation in the absence of oxidative stress. Activated phospholipase C generates inositol-1,4,5-trisphosphate (IP3) and Ca²⁺ release from internal stores. We found that both IP3-receptor inhibition and intracellular Ca²⁺ chelation prevented cyclin D1 degradation induced by oxidative stress. Furthermore, Ca²⁺ increase was transduced by Ca²⁺/calmodulin-dependent protein kinase (CaMK). In fact, H₂O₂ stimulated CaMK activity, CaMK inhibitors prevented H₂O₂-induced cyclin D1 down-modulation, and CaMK overexpression induced cyclin D1 degradation. Finally, overriding of cyclin D1 down-modulation via its forced overexpression or via CaMK inhibition increased cell sensitivity to H₂O₂-induced apoptotic cell death. Thus, cyclin D1 degradation enhances endothelial cell survival on oxidative stress.--Fasanaro, P., Magenta, A., Zaccagnini, G., Cicchillitti, L., Fucile, S., Eusebi, F., Biglioli, P., Capogrossi, M. C., Martelli, F. Cyclin D1 degradation enhances endothelial cell survival upon oxidative stress.