Increased mitogenic signaling by positive effectors such as Ras or Myc can 
trigger senescence in normal cells, a response believed to function as a 
tumor-suppressive mechanism. We report here the existence of a checkpoint that 
monitors hypoproliferative signaling imbalances. Normal human fibroblasts with 
one copy of the c-myc gene inactivated by targeted homologous recombination 
switched with an increased frequency to a telomere-independent senescent state 
mediated by the cyclin-dependent kinase inhibitor p16(INK4a). p16(INK4a) 
expression was regulated by the Polycomb group repressor Bmi-1, which we show is 
a direct transcriptional target of c-Myc. The Myc-Bmi circuit provides a 
mechanism for the conversion of environmental inputs that converge on c-Myc into 
discrete cell-fate decisions coupled to cell-cycle recruitment. A mechanism for 
limiting the proliferation of damaged or otherwise physiologically compromised 
cells would be expected to have important consequences on the generation of 
replicatively senescent cells during organismal aging.