Reactive oxygen species modulate cell fate in a context-dependent manner. Sublethal doses of H2O2 decreased the level of proliferating cell nuclear antigen (PCNA) in normal cells (including primary human dermal fibroblasts and IMR-90 cells) without affecting cyclin-dependent kinase 2 (CDK2) activity, leading to cell cycle arrest and subsequent senescence. In contrast, exposure of cancer cells (such as HeLa and MCF7 cells) to H2O2 increased CDK2 activity with no accompanying change in the PCNA level, leading to cell proliferation. A CDK2 inhibitor, CVT-313, prevented H2O2-induced cancer cell proliferation. These results support the notion that the cyclin/CDK2/p21(Cip1)/PCNA complex plays an important role as a regulator of cell fate decisions. (C) 2012 Elsevier Inc. All rights reserved.