Deregulation of Myc-family oncoproteins/transcription factors is frequently observed in human cancers and often strongly correlates with poor prognosis, emphasizing the urge to find ways of inhibiting Myc function.Here we present data suggesting that cyclin E/cyclin-dependent kinase 2 (Cdk2) phosphorylates c-Myc on Ser 62, resulting in Myc stabilization and increased Myc activity.This is counteracted by induced expression the Cdk inhibitor p27Kip 1 in response to growth inhibitory signals, resulting in increased Myc turnover, repression of Myc target genes, differentiation and senescence in Myc-transformed leukemic cells.These effects ofp27Kipl can be mimicked by small molecule inhibitors of Cdk2.